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GLI-Similar 3(GLIS3) Knock Out (KO) Mice as Models to Screen Therapeutics for Diabetes, Polycystic Kidney Disease, and Hypothyroidism

Tue, 15 May 2012 04:00:00 GMT

GLI-similar (Glis) 1-3 proteins constitute a subfamily of the Krüppel-like zinc finger transcription factors that are closely related to the Gli family. Mutations in human GLIS3 have been implicated in a syndrome characterized by neonatal diabetes and congenital hypothyroidism (NDH) and in some patients accompanied by polycystic kidney disease, glaucoma, and liver fibrosis. To further identify and study the physiological functions of GLIS3, NIEHS investigators generated mice in which GLIS3 is ubiquitously knocked out (GLIS3-KO) or conditionally knocked out in a cell type-specific manner. GLIS3-KO mice develop polycystic kidney disease, hypothyroidism, and neonatal diabetes, as indicated by the development of hyperglycemia and hypoinsulinemia. The pancreatic endocrine cells, particularly insulin-producing pancreatic beta cells, are greatly diminished in these mice. The pancreas-selective knockout mice GLIS3(Pdx1-Cre) develop severe diabetes within 2-3 months, much later than the GLIS3-KO mice. The kidney-selective knockout of GLIS3 (GLIS3(Ksp-Cre) mice lack expression of GLIS3 in the collecting ducts and develop severe polycystic kidney disease within a period of 2-4 months. These mice can be used as models to screen therapeutics for diabetes, polycystic kidney disease, and hypothyroidism. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize GLIS3 Knock Out Mice. For collaboration opportunities, please contact Elizabeth M. Denholm, Ph.D. at denholme@niehs.nih.gov.

Methods for Selection of Cancer Patients and Predicting Efficacy of Combination Therapy with Histone Deacetylase (HDAC) and mTOR Inhibitors

Tue, 15 May 2012 08:00:00 GMT

Available for licensing is a novel gene signature of thirty-seven drug responsive genes that links changes in gene expression to the clinically desirable outcome of improved overall survival. Expression of these genes has been linked to prognosis in several cancers, including, but not limited to multiple myeloma, lung, breast, and melanoma. Patients identified by this signature would be predicted to benefit from combined HDAC inhibitor/mTOR inhibitor therapy. Additional information is available upon request. CRADA Opportunity: The NCI Center for Cancer Research, Laboratory of Cancer Biology and Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Methods for Selecting Cancer Patients for HDACi/mTORi Combination Therapy. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov.

Human DNA Polymerase Gamma for Testing the Effect of Drugs on Mitochondrial Function

Wed, 09 May 2012 12:00:00 GMT

One of the primary means for treating HIV infection is the use of antiviral nucleotide or nucleoside analogs. These analogs work by inhibiting the activity of reverse transcriptase, the enzyme responsible for preparing the HIV genome for integration into the DNA of the host cell. Although these analogs do not have an effect on the polymerases responsible for replicating the human genome, the polymerase responsible for replicating the mitochondrial genome is sensitive to these analogs. When patients are exposed to nucleotide or nucleoside analogs through long-term treatment regimens, the replication of the mitochondrial genome can be adversely affected. Since mitochondrial functionality is necessary for cell activity, the nucleotide and nucleoside analogs can cause serious and unwanted side-effects.

This invention concerns the cloning and purification of human DNA polymerase gamma, the polymerase responsible for replicating the mitochondrial genome. The enzymes that have been purified include the wild-type version, a version which lacks exonuclease (proofreading) activity, and several versions with modified activity due to the mutation of the enzyme. These purified enzymes can be used to directly test the effects of new drugs that affect the activity of polymerases, such as nucleotide and nucleoside analogs. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the antibodies. For collaboration opportunities, please contact Elizabeth Denholm at denholme@niehs.nih.gov.

Multilayer X-Ray Transmission Grating Array for Phase-Contrast Imaging and Tomography

Wed, 09 May 2012 16:00:00 GMT

Classical X-ray Computed Tomography (CT) and radiography are based on X-ray absorption and cannot show soft tissue structures as well as Magnetic Resonance Imaging (MRI). Detecting the phase delay/advance of X-rays that travel through the body could enhance soft tissue contrast 10 - 100 times. Submicron-period X-ray transmission gratings for medical x-ray energies can substantially enhance the phase detection sensitivity, but fabrication is a great challenge. This invention includes a method to fabricate multilayer transmission gratings of large areas. The design uses multilayer deposition of alternating materials on a staircase substrate to form micro grating arrays of extremely small periods and high aspect ratio in large areas. This invention should substantially improve the visibility of soft tissue structures and reduce radiation dose to patients. CRADA Opportunity: The Imaging Physics Lab, Biophysics and Biochemistry Center, NHLBI/NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize multilayer-coated gratings for phase-contrast CT. For collaboration opportunities, please contact Dr. Han Wen at wenh@nhlbi.nih.gov.

Transgenic Hspa2-Cre Mice for Studying Spermatogenesis and Male Infertility

Fri, 04 May 2012 20:00:00 GMT

HSPA2 is a member of the HSP70 family of heat-shock proteins that serve as molecular chaperones. Hspa2-cre expression mimics the spermatogenic cell-specific expression of endogenous HSPA2 within the testis, being first observed in leptotene/zygotene spermatocytes. Expression of the transgene is also detected at restricted sites in the brain, as occurs for endogenous HSPA2.

Researchers at NIEHS developed the first transgenic mouse line that expresses Cre-recombinase under the control of the promoter of the heat shock protein A2 (Hspa2) gene. Expression of the Hspa2-Cre transgene during meiosis in male germ cells makes these mice a useful tool for defining the roles of genes expressed at different times during spermatogenesis or expressed in spermatogenic cells. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this mouse strain. For collaboration opportunities, please contact Elizabeth Denholm, Ph.D. at denholme@niehs.nih.gov.

Hspa2 Knockout Mice for Study of Spermatogenesis and Male Infertility

Sat, 05 May 2012 00:00:00 GMT

HSPA2 is a member of the HSP70 family of heat-shock proteins that serve as molecular chaperones. Researchers discovered that HSPA2 protein is expressed in spermatogenesis during the meiotic phase. Spermatogenic cells lacking the HSPA2 protein arrest in mid-meiosis and undergo apoptosis. HSPA2 is present in the synaptonemal complex of wild-type mice and the chromosomes fail to separate in HSPA2-deficient mice (previously known as Hsp70-2-/- mice), suggesting that HSPA2 is required for the chromosomal events of meiosis such as synapsis, crossing over, or recombination.

Researchers at NIEHS developed a knockout strain of mice in which the heat shock protein gene (Hspa2) is disrupted. This mouse model is useful in studying the process of spermatogenesis and the influence of various environmental toxins or drugs on sperm production and male infertility. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this mouse strain. For collaboration opportunities, please contact Elizabeth Denholm, Ph.D. at denholme@niehs.nih.gov.

Novel Reduced Toxicity Tropolone Derivative Compounds That Have Anti-Viral Activity Through Inhibiting RNase H Activity

Tue, 01 May 2012 04:00:00 GMT

Several novel tropolone derivatives have been identified that inhibit HIV-1 RNase H function and have potential for anti-viral activity due to reduced cellular toxicity. Inhibiting RNase H function is a potential treatment for many viral infections, since RNase H function is essential for viral replication for many pathogenic retroviruses such as HIV-1 and HIV-2. Although many hydroxytropolone compounds are potent RNase H inhibitors biding at the enzymatic active site, they are limited as therapeutic candidates by their toxicity in mammalian cells. The toxicity thought to be a result of inhibition of multiple essential mammalian metalloenzymes. We reasoned that the potential beneficial application of tropolone RNase H inhibition might be of therapeutic use if the toxic effects in mammalian cell were eliminated. By selectively adding steric bulk to add new drug-enzyme contacts for the RNase H active site, a number of novel compounds, that have initially demonstrated reduced cytotoxicity, have been produced. Importantly, these novel compounds appear to retain antiviral activity essential for use as therapeutics. CRADA Opportunity: The Molecular Targets Laboratory, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize antiviral tropolone derivatives developed by systematic medicinal chemistry on the lead series. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

A Broadly Neutralizing Human Anti-HIV Monoclonal Antibody (10E8) Capable of Neutralizing Most HIV-1 Strains

Tue, 01 May 2012 08:00:00 GMT

This Human Anti-HIV Monoclonal Antibody (10E8) has great potential to provide passive protection from infection, as a therapeutic vaccine, or as a tool for the development of vaccine immunogens. 10E8 is one of the most potent HIV-neutralizing antibodies isolated thus far and it can potently neutralize up to 98% of genetically diverse HIV-1 strains. 10E8 is specific to the membrane-proximal external region (MPER) of the HIV envelope protein, GP41. It is anticipated that 10E8 could be used in combination with another human anti-HIV-1 monoclonal antibody to provide an antibody response that neutralizes nearly all strains of HIV-1. Additionally, 10E8 is a useful tool for the design of vaccine immunogens that can elicit an adaptive immune response to produces 10E8 like antibodies. This technology also includes monoclonal antibodies from the same germ line as 10E8. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize vaccine immunogens capable of eliciting a 10E8-like adaptive immune response. For collaboration opportunities, please contact Bill Ronnenberg at 301-451-3522 or wronnenberg@niaid.nih.gov.

Chimeric Antigen Receptors that Recognize BCMA/ CD269 for Treating Multiple Myeloma

Mon, 30 Apr 2012 12:00:00 GMT

Available for licensing are chimeric antigen receptors (CARs) that specifically target B-cell maturation antigen (BCMA, CD269), a protein that is highly expressed on the surface of multiple myeloma cells. Multiple myeloma is a malignancy of plasma cells. It is almost always incurable.

A CAR is a fusion protein that can recognize a specific protein on a tumor cell and activate an adaptive immune response to attack the tumor cell. When cultured with multiple myeloma cells in vitro, T-cells engineered to express the CARs were able to induce cell death in the myeloma cells. CARs currently are being evaluated in clinical trials as a promising new area of cancer therapy. The technology available for licensing includes vectors incorporating the CARs, as well as methods of destroying multiple myeloma cells using T-cells engineered to express a CAR. CRADA Opportunity: The National Cancer Institute, Experimental Transplantation and Immunology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize chimeric antigen receptors to genetically-modify T cells to recognize BCMA/ CD269. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov.

Monoclonal Antibodies Targeting Human DNA Polymerase beta, a DNA Repair Enzyme

Thu, 19 Apr 2012 16:00:00 GMT

Available for licensing are monoclonal antibodies targeting human DNA polymerase beta (Pol B). Pol B is a constitutively expressed "housekeeping" enzyme that plays a role in base excision repair (BER), a cellular defense mechanism that repairs DNA base damage and loss. Aberrant Pol B expression is associated with genomic instability indicating that Pol B is required for DNA maintenance, replication and recombination.

These antibodies can be utilized to elucidate BER's mechanism of action and Pol B's structure and function. Moreover, the antibodies can be used to detect Pol B in samples with a variety of techniques including immunoblotting, ELISA, immunoprecipitation, and immunohistochemistry. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize these monoclonal antibodies. For collaboration opportunities, please contact Elizabeth M. Denholm, Ph.D. at denholme@niehs.nih.gov.

Cytochromes P450 CYP2J and CYP2C Polyclonal Antibodies and Recombinant Proteins

Wed, 18 Apr 2012 20:00:00 GMT

The National Institutes of Health announces polyclonal antibodies against mouse cytochrome P450s CYP2J and CYP2C. Cytochrome P450s catalyze the metabolism of a wide range of exogenous compounds, including drugs, industrial chemicals, environmental pollutants, and carcinogens. The 2C family of cytochrome P450 metabolizes an extensive number of drugs which include tolbutamide, S-Warfarin, mephenytoin, diazepam and taxol. Many of the P450 enzymes are also active in the NADPH-dependent oxidation of arachidonic acid to various eicosanoids found in several species. The 2J family is expressed at high levels in the heart and has been shown to metabolize both arachidonic acid and linoleic acid. The CYP2J and CYP2C subfamily members have a wide tissue distribution and may be useful as model systems for studies of cardiovascular disease, drug metabolism and toxicity.

Recombinant proteins of mouse cytochrome P450s CYP2C and CYP2J have also been expressed and can be used as controls in immunoblotting, as well as for metabolism studies. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize antibodies against mouse cytochrome P450s CYP2J and CYP2C. For collaboration opportunities, please contact Elizabeth M. Denholm, Ph.D. at denholme@niehs.nih.gov.

Treatment of Acute and Chronic Neurological Disorders Using GLP-1, Exendin-4 and Analogs

Thu, 19 Apr 2012 00:00:00 GMT

Glucagon-like peptide-1 (GLP-1) and related peptides, including exendin-4 and liraglutide, are incretin mimetics that enhance glucose-dependent insulin secretion following food ingestion as a regulator of glucose homeostasis. Exendin-4 and liraglutide are used clinically in the safe and effective treatment of type 2 diabetes to enhance insulin secretion and maintain a euglycemic state. These actions are primarily mediated at the level of the GLP-1 receptor in the pancreas; however, these compounds are known to enter the brain where the GLP-1 receptor also is expressed.

Researchers at the NIH have discovered the novel use of GLP-1 and exendin-4 analogs in the treatment of acute and chronic neurological disorders and neurodegenerative diseases. Studies conducted in extensive cell culture and in mouse models using these analogs have demonstrated significant neurotrophic and neuroprotective actions in models of several disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS, stroke, head trauma and peripheral neuropathy. These studies have now been extensively published and independently validated by other scientific groups. Furthermore, clinical studies are ongoing to evaluate the use of GLP-1 receptor agonists for the treatment of early Alzheimer's disease, Parkinson's disease and diabetic neuropathy by several groups within the US and Europe. CRADA Opportunity: The National Institute on Aging, Drug Design and Development Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact Vio Conley at conleyv@mail.nih.gov.

Nonpathogenic Bacteria, Paenibacillus alvei, Useful as a Natural Biocontrol Agent for Elimination of Food-borne Pathogenic Bacteria

Mon, 09 Apr 2012 04:00:00 GMT

This newly isolated non-pathogenic bacterial strain (TS-15) has shown the ability to kill or inhibit a wide variety of harmful bacteria including many of the most common food-borne pathogens such as Salmonella, Escherichia, Listeria, Shigella, Enterobacter and Staphylococcus. The TS-15 stain may provide a natural low cost means to help protect the food supply. The strain may be used as a biocontrol agent in the form of a pesticide or pretreatment to soils in which fruits and vegetable are grown. Preventative use of the TS-15 strain in biocontrol measures may prevent many of the millions of illnesses in the U.S. that are caused by food-borne pathogens each year. Such prevention may also reduce the associated costs of treatment for such illnesses. Furthermore, isolation and development of the antibiotic compounds produced by the TS-15 strain may yield useful new compositions to help treat bacterial illness, including infections by some pathogens resistant to standard antibiotics. CRADA Opportunity: The FDA Center for Food Safety and Applied Nutrition is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Paenibacillus alvei (TS-15). For collaboration opportunities, please contact Alice Welch at alice.welch@fda.hhs.gov.

Potential Use of anti-IgE in the Treatment of Lupus Nephritis

Tue, 27 Mar 2012 08:00:00 GMT

Systemic lupus erythematosus (SLE) is a multi-organ inflammatory disease characterized by a significant morbidity and mortality related to both disease evolution as well as therapeutic side effects. At least half of SLE patients develop lupus nephritis.

The inventors have used a Lyn -/- mouse model that develops an autoimmune disease exhibiting some features of human SLE. Using this model the inventors identified basophils and self-reactive IgEs as important components in the development of autoantibody-mediated kidney disease. The inventors found that depletion of basophils or the absence of IgE causes a considerable reduction in autoantibody production and preserves kidney function in the Lyn -/- mice. The inventors' work demonstrates that IgE immune complexes can activate basophils and that removal of self-reactive IgEs that form functional circulating immune complexes prevents kidney disease. Further, the inventors have shown that basophils are contributors to the production of the self-reactive antibodies that cause lupus-like nephritis in the Lyn -/- mice. Accordingly, reducing circulating IgE levels or reducing basophil activation may be of therapeutic benefit. CRADA Opportunity: The National Institute of Arthritis and Musculoskeletal and Skin Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the technology for the use of anti-IgE in the treatment of Lupus Nephritis. For collaboration opportunities, please contact Cecilia Pazman at pazmance@mail.nih.gov.

Novel Diagnostic, Prognostic and Therapeutic Biomarker for Hepatocellular Carcinoma

Tue, 27 Mar 2012 12:00:00 GMT

Scientists at the National Cancer Institute have discovered that Stearol-CoA desaturase-1 (SCD-1) is associated with hepatocellular carcinoma (HCC). Utilizing a microarray to analyze HCC patient samples, the investigators found SCD-1 is elevated in liver tumor tissues and it is a marker for a highly aggressive form of HCC, hepatic stem cell-like HCC subtype (HpSC HCC), which retains stem-cell features capable of cellular plasticity and cell motility. The investigators found SCD-1 is significantly elevated in HpSC tumors in comparison to less aggressive HCC tumors and it is associated with poor patient survival. In vitro studies demonstrate SCD-1 inhibition and/or addition of saturated palmitic acid reduces HpSC HCC characteristics. In addition to diagnostic, prognostic, and treatment applications, this technology may enable clinicians to effectively stratify patients for more aggressive cancer treatment and prioritize candidates for liver transplantation. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize biomarkers for liver cancer. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors

Tue, 27 Mar 2012 16:00:00 GMT

The MUC-1 tumor associated antigen has been shown to be overexpressed and/or underglycosylated in a wide range of human cancers. The C-terminus region of MUC-1 (MUC-1C) has been shown to be an oncogene and has been associated with a more aggressive phenotype in several different cancers.

Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope. The agonist epitopes span both the VNTR region of MUC-1 and the C-terminus region. The epitopes encompass 2 major MHC alleles reflecting the majority of the population.

Along with the method of use, the technology encompasses the use of these agonist epitopes in peptide- and protein-based vaccines, with dendritic cells or other antigen presenting cells, or encoding sequences in DNA, viral, bacterial, yeast, or other types of vectors, or to stimulate T-cells in vitro for adoptive immunotherapy protocols. CRADA Opportunity: The Laboratory of Tumor Immunology and Biology, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the use of MUC-1 tumor antigen agonist epitopes for the treatment or prevention of cancer. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

A Novel, Non-invasive Test for the Detection of Chromaffin Cell Tumors Associated with SDHB Mutation

Fri, 23 Mar 2012 20:00:00 GMT

Pheochromocytomas/ paragangliomas (PHEOs/PGLs) are hormone producing tumors of the sympathetic nervous system located in the adrenal glands (which sit atop the kidneys) or the paraganglia, which are distributed throughout the upper body. Mutations in the gene of a mitochondrial protein, succinate dehydrogenase B (SDHB), can cause PHEOs/PGLs that have a high rate of malignancy. Normally, PHEOs/PGLs can be diagnosed by measuring increased stress hormone metabolites in blood or urine. However, detection of SDHB-related PHEOs/PGLs can be difficult as up to ten percent do not show elevated stress hormone metabolites, and thus proper diagnosis requires expensive and often not-widely-available imaging. In addition, SDHB-PHEO/PGL patients need regular imaging to rule out development of metastases and family members of patients with SDHB-PHEOs/PGLs need genetic testing for risk evaluation. A significant need remains for additional diagnostic methods to prevent misdiagnosis of patients with non-secreting or metastatic SDHB-PHEOs/PGLs and risk evaluation of family members.

Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) have developed methods to identify SDHB mutation based on the presence/ absence of just four urinary peptides. Further data from the researchers suggests that metastatic PGLs can also be identified in patients based on their urinary peptide pattern. CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize a urine-based diagnostic to detect proteins associated with pheochromocytoma/paraganglioma (PHEO/PGL). For collaboration opportunities, please contact Joseph M. Conrad III, Ph.D., J.D. at jmconrad@mail.nih.gov.

Use of Englerin A, a Small Molecule HSF1 Activator, for the Treatment of Diabetes, Obesity, and Other Diseases Associated with Insulin Resistance

Sat, 24 Mar 2012 00:00:00 GMT

Insulin resistance is a causative factor for type 2 diabetes, obesity and a number of other conditions. This technology claims methods for treating diseases or conditions associated with insulin resistance using the small molecule epoxy-guaiane derivative englerin A and related compounds. The compounds are claimed separately in a related NIH technology.

The inventors have shown that englerin A, a compound originally isolated from the Phyllanthus plant and previously identified as an anti-cancer agent, can also be used to treat insulin resistance. Insulin resistance is associated with reduced gene expression and production of heat shock protein 70 (HSP70). Using a mouse with tumor model, the inventors discovered that administration of englerin A decreases blood glucose levels by activating transcription of HSF1, thereby increasing the expression and secretion of HSP70. Thus, englerin A and related compounds represent potential drugs for the treatment of a variety of conditions associated with insulin resistance. CRADA Opportunity: The NCI Urologic Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize epoxyguaianes as anti-type 2 diabetes agents. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov.

Direct Impact Spark Ionization (DISI) Mass Spectrometry (MS) for Identification of Microbes

Fri, 23 Mar 2012 04:00:00 GMT

Generating reproducible mass spectra from bacterial samples in a timely fashion at atmospheric pressure remained problematic for many years. FDA/NCTR inventors designed a rapid mass spectrometry device using direct impact spark ionization source for microbial analytes identification via spectral pattern recognition. The device design includes a rapid mass spectrometer suitable for analyzing microbiological samples that was earlier used to analyze low volatile organic compounds. The device employs a solid needle for electrode discharge. It includes a gear plate that introduces stainless steel pins carrying bacterial samples. The pins also act as counter electrodes and are targeted by controlled arcs. The small custom-made glass cylinder that is meant to shut out oxygen and prevent the introduction of ambient moisture into the analyte is unique from other DISI device. The examination revealed enormous peak intensity and spectral information with normal ionization mode on the same instrument. This device can be employed in fields such as pathogen determination in clinical settings, QA/QC (of drugs, food or cosmetic ingredients), continuous monitoring of (airborne) Biological Warfare Agents and the like. CRADA Opportunity: The NCTR/FDA inventors are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this device. For collaboration opportunities, please contact Alice Y. Welch, Ph.D. at Alice.Welch@fda.hhs.gov.

Personalized Body Weight Management System Using Monitoring Devices and Mathematical Models of Metabolism

Fri, 23 Mar 2012 08:00:00 GMT

Attempts to manage body weight are often unsuccessful or only temporary. This is, in part, due to antiquated dieting methods that attempt to address calorie consumption while ignoring metabolic and physical changes. It is becoming clear that personalized methods to manage body weight must be developed.

Scientists at the NIH have developed new methods for prescribing and monitoring personalized weight management interventions. The system uses validated mathematical models of human metabolism to set weight management goals and predict individual body weight outcomes in the context of changing metabolic needs and calorie consumption. The system uses repeated monitoring of a patient's body weight to assess progress and provide specific feedback to the patient and health care professional. Projected outcomes and body weight goals can be revised over time along with required prescription modifications to meet the body weight goals. The system is integrated into a network of one or more devices that may additionally monitor various physiological parameters, physical activities, food intake, or other behaviors. Such an enhanced personalized weight management program has great promise in the management of obesity. CRADA Opportunity: The NIDDK Laboratory of Biological Modeling is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact Marguerite J. Miller at 301-496-9003 or millermarg@niddk.nih.gov.

The Cancer Stem Cell Finder: A Novel Reporter Construct which uses Transposition and Green Fluorescent Protein Expression to identify Cancer Stem Cells

Fri, 02 Mar 2012 13:00:00 GMT

Scientists at the National Institutes of Health (NIH) have designed a novel reporter construct which can be used to identify, monitor, and allow for the manipulation of cancer stem cells (CSCs). CSCs are a subset of poorly differentiated tumor cells expressed at low frequency within a tumor and are resistant to conventional chemotherapies. CSCs have high metastatic potential and give rise to new tumors that spread cancer throughout the body. These characteristics make CSCs prime targets for developing new therapeutic agents to eradicate cancer.

The reporter construct is a novel expression vector composed of the Sleeping Beauty transposon plasmid and a Nanog promoter linked to green fluorescent protein (GFP). Nanog is a transcription factor that is overexpressed in embryonic stem (ES) cells and tumors that resemble ES cells. When introduced into a population of tumor cells, the Nanog-GFP-Sleeping Beauty transposon construct is able to integrate into tumor cell DNA via transposition. If the transposed cell is a CSC, the Nanog transcription factor overexpressed in that CSC will bind to the Nanog-promoter in the reporter construct to drive GFP expression within the cell. Thus, CSCs can be isolated based on their selective expression of the GFP label. The NIH scientists have utilized their reporter construct to identify small populations of CSCs in mouse and human breast cancer cell models. CRADA Opportunity: The Cancer and Inflammation Program, NCI, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Nanog promoter driven GFP constructs for the easy identification and isolation of cancer stem cells. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

Small-Molecule Inhibitors of Human Galactokinase for the Treatment of Galactosemia and Cancers

Fri, 02 Mar 2012 18:00:00 GMT

Lactose, found in dairy products and other foods, is comprised of two simple sugars, glucose and galactose. In galactosemia, where galactose is not properly metabolized, build-up of toxic compounds, such as galactose-1-phosphate, can lead to liver disease, renal failure, cataracts, brain damage, and even death if this disorder is left untreated. Currently, the only treatment for galactosemia is elimination of lactose and galactose from the diet, but in some cases this is not sufficient to avoid long-term complications from the disorder.

This technology describes selective small-molecule inhibitors of human galactokinase, which inhibit the first step in galactose metabolism. These compounds could be used to treat galactosemia by eliminating the build-up of toxic metabolites in brain, liver and other tissues, and could form the basis for the first effective treatment for this disorder.

These inhibitors are also promising candidates for the treatment of certain cancers, such as PTEN/AKT misregulated cancers. The inventors have already shown that the inhibitors are cytotoxic for several cancer cell lines. CRADA Opportunity: The National Center for Advancing Translational Sciences is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Small-Molecule Inhibitors of Human Galactokinase for the Treatment of Galactosemia and Cancers. For collaboration opportunities, please contact Lili M. Portilla, MPA at portilll@mail.nih.gov.

Novel Radio-labeled Agents for Imaging Alzheimer's Disease-associated Amyloid

Mon, 27 Feb 2012 23:00:00 GMT

This technology introduces novel radio-labeled agents for imaging amyloid deposits in the brains of Alzheimer's Disease patients. These are small molecule, radio-ligand compounds that are analogs of benzo[d]thiazole. They are highly specific to amyloid, have low background noise, do not undergo rapid defluoridation and do not produce residual radioactivity in the brain. In addition, the compounds are stable and may be readily synthesized from commercially available starting materials. These compounds may be used in many noninvasive imaging techniques including: magnetic resonance spectroscopy (MRS) or imaging (MRI), or positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to measure amyloid. Non-invasive detection of Alzheimer's disease-associated amyloid plaques in the brain would be valuable for early diagnosis, monitoring, and for clinical development of therapeutic drugs. CRADA Opportunity: The National Institute of Mental Health (NIMH) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Beta-amyloid Imaging Agents. For collaboration opportunities, please contact Suzanne L. Winfield, Ph.D. at winfiels@intra.nimh.nih.gov or 301-402-4324.

A Method of Identifying Cdk5/p35 Modulators, and Possible Diagnostic or Therapeutic Uses for Neurodegenerative Diseases

Sat, 25 Feb 2012 04:00:00 GMT

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine cyclin-dependent kinase that is highly expressed in the central nervous system and controls many biological processes that impact learning and memory, as well as pain and drug addiction. Studies have indicated that abnormal Cdk5 activity may be associated with the onset of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). The kinase activity of Cdk5 is turned on when it binds to one of the two proteins considered to be neuronal activators, p35 and p39.

Scientists at the NIH designed a cell-based assay to screen for p35 transcriptional regulators that work as upstream regulators of Cdk5. This technology may be useful for assessing the presence and risk of conditions associated with atypical Cdk5 kinase activity or for finding drug modulators that could be promising drug targets. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Laboratory of Cell and Developmental Biology, Functional Genomics Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

A Highly Potent Human sRAGE Protein for Treating Vascular Disease, Injury, or Inflammation

Thu, 23 Feb 2012 09:00:00 GMT

The receptor for advanced glycation end products (RAGE) is a cell surface protein that triggers signaling pathways leading to inflammation. RAGE-stimulated inflammation can contribute to adverse vascular conditions, such as atherosclerosis and restenosis. The soluble version of RAGE (sRAGE) binds the same target molecules (advanced glycation end products), but cannot activate inflammatory signaling pathways. For this reason, sRAGE is thought to act as a decoy for RAGE. sRAGE reduces inflammation and pathogenic consequences associated with RAGE signaling. The administration of sRAGE has been used to treat atherosclerosis and arterial restenosis in animal models. The inventors established a way to produce human sRAGE with more than 1000-fold greater potency than current methods. Production of full length human sRAGE in cultured mammalian cells enables addition of mammalian post-translational modifications that dramatically enhance potency. This invention covers methods of production, the resulting modified sRAGE molecules, and methods of using this highly potent sRAGE for treating adverse vascular conditions. CRADA Opportunity: The National Institute on Aging, Laboratory of Cardiovascular Science, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize sRAGE. For collaboration opportunities, please contact Vio Conley, M.S. at conleyv@mail.nih.gov. Click here to view the NIA collaborative opportunity announcement.

Use of Frizzled (Fzd) as a Biomarker for Cancer Patient Selection and Therapeutic Intervention

Thu, 23 Feb 2012 14:00:00 GMT

Personalized medicine is becoming more important in the diagnosis and treatment of diseases, particularly cancer. One signaling pathway which has been demonstrated to be involved in cancer is the Wnt/beta catenin signaling pathway. The NIH scientists associated with this technology have identified a potential new biomarker for cancer based on their investigation of the role of the secreted frizzled related proteins, sFRP's, which are known to play a role in Wnt/beta catenin signaling. In particular, the scientists have determined that different Frizzled receptors (Fzd) have different and opposite roles in Wnt/beta catenin signaling with the expression of certain Fzd receptors, e.g. Fzd5, being associated with an increase in Wnt/beta catenin signaling and the expression of other Fzd receptors, e.g., Fzd2, being associated with a decrease in Wnt/beta catenin signaling. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Regulation of Wnt and Frizzled signaling by secreted Frizzled-related proteins. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov.

miR126 for the Mobilization of Hematopoietic Stem/Progenitor Cells (HSPCs) into Peripheral Blood

Thu, 23 Feb 2012 19:00:00 GMT

The NIH inventors have discovered that a micro RNA, miR126, mobilizes hematopoietic stem/progenitor cells (HSPCs) from the bone marrow into blood. These mobilized HSPCs can be easily collected from blood and used for reconstitution of ablated or functionally-impaired bone marrow. miR126 may also facilitate mobilization of bone-resident cancer cells into the circulation where they could be more easily targeted by cancer therapeutics. This discovery could replace bone marrow transplantation as we do it today. Rather than using the current non-selective agent G-CSF (which preferentially mobilizes mature myeloid cells rather than stem/progenitor cells), miR126 could be used for selective mobilization of the HSPCs needed for hematopoietic cell transplantation. Additionally, miR126 could be used to mobilize malignant cells from the bone marrow and render them more easy targets for therapy. It was previously shown that the bone marrow cavity promotes the survival of many cells including tumor cells, and that such cells may easily die when removed from the bone marrow niche and moved to the blood. Therefore, this discovery could also change treatment of many cancers that arise within the bone marrow or metastasize to the bone. Since the mechanism by which miR126 promotes HSPCs/tumor cell mobilization is attributable to the inhibition of VCAM-1 expression, miR126 could be used to treat inflammatory states where the expression of VCAM1 provides an anchor for inflammatory cells at sites of inflammation. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize miR126 and Mobilization of Hematopoietic Stem/Progenitor Cells. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

A New Class of Broad-spectrum Antibiotics: Naturally-occurring Chrysophaetins and Their Analogues

Thu, 23 Feb 2012 00:00:00 GMT

Non-toxic Compounds that Inhibit the Formation and Spreading of Tumors

Wed, 22 Feb 2012 05:00:00 GMT

Available for licensing are novel pyrrolopyrimidine compounds that disrupt the assembly of the perinucleolar compartment (PNC), a sub-nuclear structure highly prevalent in metastatic tumors. These notable compounds act without overt cytotoxicity.

The presence of the PNC positively correlates with metastatic capacity, making it a potential marker for cancer development and prognosis. These compounds could also serve as useful tools to elucidate the biology driving the formation and maintenance of the PNC, and unravel its association with metastasis. CRADA Opportunity: The National Center for Advancing Translational Sciences is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact Lili M. Portilla, MPA at 301-217-2589 or Lilip@nih.gov.

Antagonists of the Hedgehog Pathway as Therapeutics for the Treatment of Heterotopic Ossification, Vascular Calcification, and Pathologic Mineralization

Mon, 13 Feb 2012 10:00:00 GMT

Heterotopic ossification (HO) results from osteoid formation of mature lamellar bone in soft tissue sites outside the skeletal periosteum (skeletal system), most commonly around proximal limb joints. HO can also be caused by genetic diseases such as progressive osseous heteroplasia (POH) and fibrodysplasia ossificans progressiva (FOP). Currently, all forms of HO lack adequate treatments and definite cure. Vascular calcification is a complex process that involves biomineralization and resembles osteogenesis. It is exacerbated during such conditions as diabetes, osteoporosis, menopause, hypertension, metabolic syndrome, chronic kidney disease, and end stage renal disease. In the present technology, the inventors describe novel methods for preventing or treating HO and vascular calcification using one or more antagonists of the Hedgehog pathway. The inventors, using both in vitro (limb culture experiments) and in vivo studies using Prx1-cre; Gsf/f mice model discovered that the antagonists of the Hedgehog pathway prevent formation of HO. The inventors also observed that Prx1-cre; Gsf/f mice developed calcification or mineralization around their blood vessels, and treatment with Hedgehog antagonists reduced mineralization throughout the body of these mice, including regions around the blood vessels, as observed by mineral staining. The antagonists that can be used to develop effective therapeutics include zerumbone epoxide, arcyriaflavin C, 5,6-dihyroxyarcyriaflavin A, physalin F, physalin B, arsenic trioxide (ATO), sodium arsenite, etc. CRADA Opportunity: The National Human Genome Research Institute (NHGRI) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize antagonists of the Hedgehog pathway for treatment of ossification and calcification disorders. For collaboration opportunities, please contact Claire T. Driscoll at 301-594-2235 or cdriscoll@mail.nih.gov.

Influenza Vaccine

Mon, 13 Feb 2012 15:00:00 GMT

It has been shown that the fusion peptide, a sequence comprised of fourteen amino acids at the N-terminal of the influenza hemagglutinin 2 protein, is conserved among A and B influenza viruses. Monoclonal antibodies against this peptide are capable of binding all influenza virus HA proteins and inhibit viral growth by impeding the fusion process between the virus and the target cell. This application claims immunogenic conjugates comprising the fusion peptide region linked to a carrier protein. In preclinical studies, these conjugates were immunogenic and induced booster responses. The induced antibodies bound to the recombinant HA protein. This methodology of linking the highly conserved fusion peptide region to a carrier protein can broaden the protective immune response to include influenza A and B virus strains. This would eliminate the need for annual influenza vaccination. CRADA Opportunity: The NICHD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize conjugate influenza vaccines comprising fusion peptide region. For collaboration opportunities, please contact Joseph Conrad, Ph.D., J.D. at 301-435-3107 or jmconrad@mail.nih.gov. Click here to view the NICHD collaborative opportunity announcement.

Chimeric Antigen Receptors to CD22 for Treating Hematological Cancers

Mon, 13 Feb 2012 20:00:00 GMT

Chimeric antigen receptors (CARs) are hybrid proteins consisting of an antibody binding fragment fused to protein signaling domains that cause some T-cells to become cytotoxic. Once activated, these cytotoxic T-cells can selectively eliminate the cells which they recognize. Thus, by engineering a T-cell to express a CAR that is specific for a certain cell surface protein, it is possible to selectively target cells for destruction. This is a promising new therapeutic approach known as adoptive cell therapy.

CD22 is a cell surface protein that is expressed on a large number of B-cell lineage hematological cancers. Several promising therapies are being developed which target CD22, including therapeutic antibodies and immunotoxins. This technology concerns the use of a high affinity antibody binding fragment to CD22 as the targeting moiety of a CAR, adding adoptive cell therapy as a new prospective treatment for certain leukemias and lymphomas. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Chimeric Antigen Receptor for CD22, High Affinity. A gene vector to target T cells to B cell leukemia and lymphoma. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

Ketamine Metabolites for the Treatment of Depression and Pain

Thu, 09 Feb 2012 01:00:00 GMT

The market continues to have a need for therapeutics for treating pain and depression that have efficacy in a high percentage of patients but have reduced anaesthetic properties and reduced abuse liability. Ketamine, a drug currently used in human anesthesia and veterinary medicine, has been shown in clinical studies to be effective in the treatment of several conditions, including the of treatment-resistant bipolar depression, major depressive disorder, neuropathic pain, and chronic pain, including complex regional pain syndrome (CRPS). However the routine use of the drug is hindered by unwanted central nervous system (CNS) effects and a patient response rate of ~70%. New data suggests that ketamine metabolites can be used with similar results but with an increase in patient response rates and a decrease in undesirable side effects. CRADA Opportunity: The National Institute on Aging, Laboratory of Clinical Investigation, Bioanalytical Chemistry and Drug Discovery Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact Nicole Guyton, Ph.D. at darackn@mail.nih.gov. Click here to view the NIA collaborative opportunity announcement.

Modulating Autophagy as a Treatment for Lysosomal Storage Diseases

Tue, 17 Jan 2012 06:00:00 GMT

Researchers at NIAMS have developed a technology for treatment of lysosomal storage diseases by inhibition of autophagy. Pompe disease is an example of a genetic lysosomal storage disease caused by a reduction or absence of acid alpha-glucosidase (GAA). Patients with Pompe disease have a lysosomal buildup of glycogen in cardiac and skeletal muscle cells and severe cardiomyopathy and skeletal muscle myopathy. Treatment of Pompe disease by GAA enzyme replacement therapy is quite ineffective for the skeletal muscle myopathy. Skeletal muscle resistance to therapy is associated with increased cellular buildup of autophagic debris. Inactivation of autophagy results in effective GAA replacement therapy and a reduction in glycogen back to normal levels. This technology provides a novel approach for the treatment of Pompe disease as well as other diseases where autophagy is a critical contributor to disease development. CRADA Opportunity: The National Institutes of Health is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the technology for disabling autophagy as a treatment for lysosomal storage diseases. For collaboration opportunities, please contact Cecilia Pazman at pazmance@mail.nih.gov.

Monospecific and Bispecific Human Monoclonal Antibodies Targeting IGF-II

Tue, 17 Jan 2012 11:00:00 GMT

The type 1 insulin-like growth factor (IGF) receptor (IGF1R) is over-expressed by many tumors and mediates proliferation, motility, and protection from apoptosis. Agents that inhibit IGF1R expression or function can potentially block tumor growth and metastasis. Its major ligands, IGF-I, and IGF-II are over-expressed by multiple tumor types. Previous studies indicate that inhibition of IGF-I, and/or IGF-II binding to its cognizant receptor negatively modulates signal transduction through the IGF pathway and concomitant cell proliferation and growth. Therefore, use of humanized or fully human antibodies against IGFs represents a valid approach to inhibit tumor growth. The present invention discloses two monoclonal antibodies, designated m610.27 and m630, and a bispecific monoclonal antibody, m660, generated by linking domains from m610.27 and m630. All three antibodies display high affinities for IGF-I and IGF-II in the pM to nM range. The antibodies inhibited signal transduction mediated by the IGF-1R interaction with IGF-I and IGF-II and blocked phosphorylation of IGF-IR and the insulin receptor. m610.27 and m630 are the first pair of human antibodies that target nonoverlapping epitopes on IGF-II. All three antibodies in an IgG1 or IgG1-like format could lead to irreversible elimination of IGF-II from circulation making it a viable candidate for cancer treatment. CRADA Opportunity: The NCI CCR Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov.

New Cholera Vaccine and Method for Conjugating Bacterial Polysaccharides to Proteins

Mon, 09 Jan 2012 16:00:00 GMT

A new conjugate vaccine for cholera has been developed. The invention includes a new method to conjugate the O-specific polysaccharide-core part of the bacterial lipopolysaccharide and protein subcomponents. Conventional technology has entailed chemical treatment of both components to introduce linkers, which made them amenable for covalent linking. The new method simplifies production by utilizing squaric acid chemistry for conjugating the free amine-containing species (e.g. polysaccharides) directly to amine-containing species (e.g. proteins) without prior modification of either component. While demonstrated in this new cholera prototype vaccine, the technology is envisioned as generally applicable, thereby streamlining a complex production process. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize conjugate vaccines. For collaboration opportunities, please contact Marguerite J. Miller, M.B.A. at 301-496-9003 or millermarg@niddk.nih.gov.

Immunogenic Tetrasaccharide of Anthrax Spores

Mon, 09 Jan 2012 21:00:00 GMT

The subject of this invention is a conjugate vaccine against Bacillus anthracis the causative agent of anthrax. Substantial effort has been made to study the structure and antigenic elements of the outermost layer of B. anthracis spores. The exosporium is fully exposed to the external environment. Analysis of isolated exosporia shows as many as 20 protein components of which the most prominent is the Bacillus collagen-like protein of anthracis (BclA), a glycoprotein that displays a unique tetrasaccharide capped at its upstream end with a novel sugar residue termed anthrose. Rabbit IgG antibodies elicited by B. anthracis spores specifically recognize this tetrasaccharide. The anthrose-containing saccharide may be linked to acceptable protein carriers using standard chemistry.

Subsequent to this work, the laboratory has demonstrated that squaric acid chemistry may be a more efficient chemistry than is currently used to connect the carbohydrate and protein portions of the vaccine. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize conjugated vaccines. For collaboration opportunities, please contact Marguerite J. Miller, M.B.A. at 301-496-9003 or millermarg@niddk.nih.gov.

Novel Small Molecules to Treat Alzheimer's Disease: Amyloid Beta Channel Blockers with Anti-inflammatory Properties

Sat, 07 Jan 2012 02:00:00 GMT

Alzheimer's Disease (AD) is a common, chronic neurodegenerative disease which is thought to be due to the neurotoxic effect of the Amyloid beta (Abeta) peptide. The inventors discovered that Abeta has intrinsic calcium channel activity, and that entry of calcium into neurons through this channel leads to neuronal cell death, playing a role in Alzheimer's Disease pathology. Consistently, Abeta channel blocking drugs act as a “cork” to save neurons from Abeta-dependent cell death. Two potent and efficacious candidate drugs, MRS2481 and its enantiomeric species MRS2485, have been discovered. Both block the Abeta channel with similar potency (ca. 500 nM) and efficacy (100%). However, inhibition by MRS2481 is easily reversible, while inhibition by MRS2485 is virtually irreversible. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize a small molecule drug to treat Alzheimer's Disease. For collaboration opportunities, please contact Marguerite J. Miller, M.B.A. at 301-496-9003 or millermarg@niddk.nih.gov.

One Step Fluorine-18 Peptide Labeling Strategy of Biological Substrates

Thu, 08 Dec 2011 07:00:00 GMT

A one-step process is now available for licensing that allows direct 18F labeling of any biological substrate that is modified with 4-nitro-3-trifluoromethyl arene. Normally, 18F labeling requires several time-consuming radio synthesis steps using prosthetic groups, resulting in a low labeling yield. Other attempts at one step labeling methods have also shown relatively low yields.

This new process eliminates time-consuming radiosynthesis steps and associated low labeling yields with a single step process that displaces a nitro group in an arene. Relatively low amounts of precursor and short time radiosynthesis times are required compared to direct peptide-labeling. Higher yields by this simplified process improve time and cost efficiencies and may make 18F labeling more amenable for automation. CRADA Opportunity: The NIBIB is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the technology for One Step Fluorine-18 Peptide Labeling Strategy of Biological Substrates. For collaboration opportunities, please contact Shawn Chen, Ph.D. at shawn.chen@nih.gov.

Mucus Shaving Apparatus for Endotracheal Tubes

Thu, 08 Dec 2011 12:00:00 GMT

HHS seeks parties interested in manufacturing and commercializing an endotracheal tube cleaning apparatus for insertion into the inside of the endotracheal tube of a patient to shave away mucus deposits. This cleaning apparatus comprises a flexible central tube with an inflatable balloon at its distal end. Affixed to the inflatable balloon are one or more silicone rubber shaving rings, each having a squared leading edge to shave away mucus accumulations implicated in bacterial accumulation. In operation, the un-inflated cleaning apparatus is inserted into the endotracheal tube until its distal end is properly aligned with the distal end of the endotracheal tube. After proper alignment, the balloon is inflated by a suitable inflation device (e.g., a syringe) until the balloon's shaving rings are pressed against the inside surface of the endotracheal tube. The cleaning apparatus is then pulled out of the endotracheal tube and in the process the balloon's shaving rings shave off the mucus deposits from the inside of the endotracheal tube. CRADA Opportunity: The NHLBI Pulmonary Critical Care Medicine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the endotracheal tube mucus cleaning device and related laboratory interests. Please contact Marianne Lynch at 301-594-4094 or lynchm@nhlbi.nih.gov for more information.

Chemotoxins for Targeted Treatment of Diseased Cells

Fri, 02 Dec 2011 17:00:00 GMT

Researchers at the National Institute on Aging (NIA) have developed a straightforward method to elicit immune responses to specific cancers and AIDS by using a chemoattractant-based antigen delivery strategy. The strategy uses formulations composed of chemokines fused to toxic moieties (aka “chemotoxins”) to preferentially and specifically eliminate chemokine receptor-expressing cells. The method uses the natural ability of the chemokines to stimulate measurable and improved humoral and immune responses.

Chemokines can be of viral or microbial (B-Defensin) origin.
This method can also be used to cause inflammation to specifically target immune cells to increase immunogenicity for malignant tumors using SPANX-B and Laminin tumor antigens.

CRADA Opportunity: The National Institute on Aging (NIA) is seeking parties interested in collaborative research to further evaluate or commercialize effective vaccines that target bacterial, viral, or tumor antigens. Any or all of the inventions in this announcement are available for co-development and collaboration. For collaboration opportunities, please contact Nikki Guyton, Ph.D. at darackn@mail.nih.gov. Click here to view the NIA collaborative opportunity announcement.

AAV Mediated CTLA-4 Gene Transfer to Treat Sjogren's Syndrome

Fri, 18 Nov 2011 22:00:00 GMT

Sjögren’s syndrome is an autoimmune disease that affects over 2 million Americans, primarily over the age of 40. One of the major outcomes of Sjögren's syndrome is xerostomia (dry mouth) that is caused by immune system attack on moisture producing salivary glands. Researchers at the National Institute of Dental and Craniofacial Research have developed a therapy that alleviates xerostomia in a murine model of Sjögren's syndrome. This technology consists of a local delivery of adeno-associated virus (AAV) mediated cytotoxic T-lymphocyte antigen 4 Immunoglobulin-G (CTLA4IgG) fusion protein to salivary glands. The system effectively blocks CTLA4 ligand interactions with T cell surface receptors, resulting in immune suppression and reversal of autoimmune-related xerostomia. Targeted delivery of the AAV-CTLA4-IgG system makes this invention a novel therapeutic for the prevention of xerostomia-associated pain and discomfort caused by Sjögren's syndrome. CRADA Opportunity: The NIDCR is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact David Bradley at bradleyda@nidcr.nih.gov.

Treatment of Tuberculosis — Adjuvant Therapies to Increase the Efficiency of Antibiotic Treatments

Sat, 19 Nov 2011 03:00:00 GMT

There is growing evidence that resistance to Mycobacterium tuberculosis infection is governed in large part by the regulation of host cell death. Lipid mediators called eicosanoids are thought to play a central role in this process. The subject invention is a novel method of enhancing the efficacy of antibiotic treatments for Mycobacterium tuberculosis infection by co-administering an inhibitor of 5-lipoxygenase and a COX-2 dependent prostaglandin. Inhibition of 5-lipoxygenase and treatment with prostaglandin E2 results in alteration of the eicosanoid balance. The synergistic effects of altering the eicosanoid balance and treatment with antibiotics is believed to result in more efficient reduction of the bacterial burden and thus, the period of antibiotic administration and antibiotic dosage could potentially be reduced. In vivo data from mouse models can be provided upon request. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize adjuvant therapy for antibiotic treatment regiments against tuberculosis. For collaboration opportunities, please contact Katrin Mayer. Ph.D. at mayerk@niaid.nih.gov or 301-594-8061.

Genetically Engineered Mouse Model for Use as an Alternative Screening Method for Evaluating P-glycoprotein (P-gp) Substrate Toxicity in Avermectin-sensitive Dogs

Fri, 18 Nov 2011 08:00:00 GMT

A pitfall to avermectins is central nervous system (CNS) toxicities in herding dogs. As a result, all new avermectins must be tested in a "Collie Safety Study" to determine the degree of CNS toxicity. The toxicity is due to a 4 base pair mutation in the ATP-binding cassette, sub-family B member 1 (ABCB1) gene. This gene encodes for the P-glycoprotein (P-gp) that affects absorption, distribution and elimination of certain drugs. Researchers at FDA have developed an alternate animal model that includes two transgenic mouse models, one containing the mutant form of the canine ABCB1 gene (Yancy 1 line) and the other containing the canine wild-type gene (Yancy 2 line). The paired mouse system can be utilized to assess the safety of avermectins and other canine drugs by determining the toxicity to canines with the mutated form of the ABCB1 gene. Ivermectin, a derivative of the avermectin family of heartworm drugs used to treat and control parasitic infections, was used to verify this mouse model. This technology will enhance the population predictions derived from clinical safety data and serve to reduce the use of dogs in avermectin derivative safety studies that are part of the Investigational New Animal Drug (INAD) approval process. CRADA Opportunity: The FDA Center for Veterinary Medicine is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this alternative mouse model. For collaboration opportunities, please contact Haile F. Yancy at haile.yancy@fda.hhs.gov or 301-210-4096.

Medical Device for Intraocular Injection of Therapeutics and Fluid Sampling

Wed, 16 Nov 2011 13:00:00 GMT

The National Institutes of Health seeks research collaboration and commercialization partners for a medical device for administering therapeutics into the eye to treat a variety of ocular diseases including diabetic retinopathy, retinal vein occlusion and macular degeneration. The device is a dual function needle that can both inject and sampling ocular fluid at the same injection site. The needle includes a hub portion in communication with a needle portion through a lumen that may be used as a conduit to inject a therapeutic into an injection site. A sample chamber, with an optional absorbent material, is disposed in the lumen capable of absorbing intraocular fluid via a passive filling action into the sample chamber. CRADA Opportunity: The National Eye Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize intraocular therapeutic delivery. For collaboration opportunities, please contact Alan E. Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov.

PANVAC — Cancer Vaccine for the Prevention and Treatment of Colorectal Cancer

Fri, 28 Oct 2011 17:00:00 GMT

Cancer immunotherapy is an approach where tumor associated antigens (TAAs), which are primarily expressed in human tumor cells, and not expressed or minimally expressed in normal tissues, are employed to generate a tumor-specific immune response. Specifically, these antigens serve as targets for the host immune system and elicit responses that results in tumor destruction. The initiation of an effective T-cell immune response to antigens requires two signals. The first one is antigen-specific via the peptide/ major histocompatibility complex and the second or “costimulatory” signal is required for cytokine production, proliferation, and other aspects of T-cell activation.

The PANVAC technology employs avirulent poxviruses to present a combination of tumor-associated antigens (TAAs) and costimulatory molecules to activate T-cells and break the immune systems tolerance towards cancer cells. This is performed using recombinant poxvirus DNA vectors that encode both T-cell costimulatory molecules and TAAs. The combination of the costimulatory molecules B7.1, ICAM–1 and LFA–3, is known as TRICOM. Recombinant poxviral vaccines (vaccinia (V) and fowlpox (F) containing TRICOM have been evaluated in prime (V)/boost (F) regimens in preclinical models and in several clinical trials in patients with metastatic colorectal cancer. Additionally, PANVAC has shown promising survival results in treating patients with metastatic colorectal cancer.

Furthermore, recombinant poxviral TRICOM based vaccines can also be employed for the prevention and/or therapy of colorectal cancer containing a range of other TAAs such as the T-box transcription factor Brachyury.

This technology is available for both licensing and collaborative research. A detailed announcement was published in the Federal Register on Thursday, October 27, 2011 (76 FR 66728), and may be viewed at http://www.gpo.gov/fdsys/pkg/FR-2011-10-27/pdf/2011-27859.pdf. CRADA Opportunity: A CRADA partner for the further codevelopment of this technology specifically in colorectal cancer is currently being sought by the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI. The CRADA partner will (a) generate and characterize recombinant poxviruses expressing specific tumor-associated antigens, cytokines, and/or T-cell costimulatory factors, (b) analyze the recombinant poxviruses containing these genes with respect to appropriate expression of the encoded gene product(s), (c) supply adequate amounts of recombinant virus stocks for preclinical testing, (d) manufacture and test selected recombinant viruses for use in human clinical trials for colorectal cancer, (e) submit Drug Master Files detailing the development, manufacture, and testing of live recombinant vaccines to support the NCI-sponsored IND and/or company-sponsored IND, (f) supply adequate amounts of clinical grade recombinant poxvirus vaccines for clinical trials conducted at the NCI Center for Cancer Research (CCR), and (g) provide adequate amounts of vaccines for extramural clinical trials, if agreed upon by the parties, and conduct clinical trials under company-sponsored or NCI-sponsored INDs. NCI will (a) provide genes of tumor-associated antigens, cytokines and other immunostimulatory molecules for incorporation into poxvirus vectors, (b) evaluate recombinant vectors in preclinical models alone and in combination therapies, and (c) conduct clinical trials for colorectal cancer of recombinant vaccines alone and in combination therapies.

Contact Michael Pollack at 301-435-3118 or email pollackm@mail.nih.gov for additional information about this CRADA opportunity.

Antiandrogen Small Molecules for the Treatment of Prostate Cancer

Fri, 21 Oct 2011 21:00:00 GMT

The present licensing opportunity is for a new class of small molecule compounds, and the method of using them to treat prostate cancer. This year it is estimated there will be over 32,000 deaths from prostate cancer showing an unmet need for a more effective treatment particularly for castrate-resistant prostate cancer (CRPC). CRPC is characterized by androgen-independent cancer cells that have adapted to the depletion of hormones and continue to grow. Abnormal androgen receptor signaling is known to drive advanced castrate-resistant prostate cancer. The small molecule compounds of the instant invention are antiandrogens that target androgen receptor signaling in both androgen-independent and androgen-sensitive androgen receptor activity, and androgen receptors that are resistant to the current antiandrogens available. Unlike the currently available antiandrogens, the new small molecules induce androgen receptor degradation and cell death in prostate cancer cells. Further, these compounds and methods can also induce degradation of other steroid hormone receptors demonstrating the possibility of treating a wider range of cancers. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Small Molecules for the Treatment of Prostate Cancer. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov or 301-496-0477.

Protease Deficient Bacillus anthracis with Improved Recombinant Protein Yield Capabilities

Sat, 22 Oct 2011 01:00:00 GMT

Species of Bacillus, such as Bacillus anthracis, Bacillus cereus, and Bacillus subtilis, are attractive microorganisms for recombinant protein production in view of their fast growth rate, high yield, and ability to secrete produced products directly into the medium. Bacillus anthracis is also attractive in view of its ability to produce anthrax toxin and ability to fold proteins correctly. This application claims a B. anthracis strain in which more than one secreted protease is inactivated by genetic modification. Such a protease-deficient B. anthracis has an improved ability to produce recombinant secreted proteins compared to other bacteria, particularly other Bacillus. Improvements include production of intact (i.e., mature full-length) proteins, often at high yield. CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize B. anthracis vaccines, B. anthracis protein production. For collaboration opportunities, please contact Charles Rainwater at 301-435-8617.

Infectious Hepatitis E Virus Genotype 3 Recombinants — Prospective Vaccine Candidates and Vector System

Thu, 06 Oct 2011 05:00:00 GMT

Infection by Hepatitis E virus (HEV) is a relevant health issue in a number of developing countries and it is also an emerging food-borne disease of industrialized countries. Genotype 1 and 2 infections are found exclusively in humans while genotype 3 and 4 viruses have been found not only in humans, but also swine, deer, mongoose, cattle, and rabbits. In particular, genotype 3 and 4 viruses are ubiquitously found in swine and undercooked pork is thought to be one of the sources of infection for cases of human infections in industrialized countries.

This technology is a recombinant, infectious genotype 3 HEV that has been adapted to grow in cell culture and can potentially be used to develop vaccines against HEV or as a vector system to insert exogenous sequences into HEV. The virus (strain Kernow-C1, genotype 3) originated from a chronically infected human subject and was adapted to grow in human hepatoma cells. The adapted virus is unique in that it contains an insertion of a portion of a human ribosomal protein in Open Reading Frame 1 of the virus. Desired exogenous sequences could potentially be placed in lieu of the insert without inactivating the virus, making the subject technology a prospective HEV vector platform. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize hepatitis E virus vaccines. For collaboration opportunities, please contact Wade Green, Ph.D. at 301-827-0258 or williamswa@niaid.nih.gov.

Human Phospho-Serine134 Glucocorticoid Receptor Polyclonal Antibody: Useful for the Characterization of Glucocorticoid Signaling Processes, e.g., in Cancer and Inflammation

Thu, 06 Oct 2011 09:00:00 GMT

The glucocorticoid receptor (GR) functions as a hormone-dependent transcription factor that is involved in the maintenance of basal and stress-related homeostasis. Serine 134 is a newly discovered phosphorylation target on the human glucocorticoid receptor that becomes phosphorylated during stress-activating conditions such as ultraviolet irradiation, nutrient starvation, and oxidative stress. The inventors have developed a rabbit polyclonal antibody that specifically recognizes the Ser 134 phosphorylated form of the human glucocorticoid receptor. This antibody may be particularly useful for a variety of basic research applications, such as the characterization and study of glucocorticoid signaling in cancer, inflammation, and other diseases.

The antibody is available as crude antisera and has been epitope purified; it has cross reactivity with human, rat, and mouse tissues. CRADA Opportunity: The NIEHS, Molecular Endocrine Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Human Phospho-Serine134 Glucocorticoid Receptor Polyclonal Antibody. Please contact Elizabeth M. Denholm at denholme@niehs.nih.gov for more information.

Diagnostic Assays and Methods of Use for Detection of Filarial Infection

Thu, 29 Sep 2011 13:00:00 GMT

The effort targeting the mosquito borne neglected tropical disease lymphatic filariasis for elimination through mass drug administration by 2020 will require accurate, cost effective methods for detecting early infections. The World Health Organization-recommended immunochromatographic test detects adult Wuchereria bancrofti (Wb) antigen in blood, but shows variable efficacy due to the complex life cycle of the parasites and cross reactivity with other organisms. This variability may hinder effective lymphatic filariasis elimination efforts. This new technology improves available detection methods through use of an isolated immunoreactive antigen, Wb123, from infective stage larvae (L3) Wb; which results in specific detection early in the infective cycle with reduced cross reactivity. This technology may see wide application in testing and surveillance of lymphatic filariasis as part of the effort to eliminate the disease worldwide. CRADA Opportunity: The National Institute of Allergy and Infectious Disease (NIAID) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Diagnostic Assays and Methods of Use for Detection of Filarial Infection. For collaboration opportunities, please contact Johanna Schneider, Ph.D. at Schneiderjs@niaid.nih.gov or 301-451-9824.

Rapid Molecular Assays for Specific Detection and Quantitation of Loa Loa Microfilaremia

Thu, 29 Sep 2011 17:00:00 GMT

The risk of fatal reactions in some infected individuals administered drug treatments for Loa loa infection, and the lack of accurate, convenient, diagnostics for this infection have thwarted efforts to eradicate the disease. Time consuming, labor intensive and training intensive microscope-based analysis of blood samples is the standard available diagnostic for Loa loa infection. This new assay technology introduces an easy to use, species-specific, highly sensitive, diagnostic that is able to be performed with minimal training. Positive test results may be indicated by an easily visualized color change and this test may be run without the need for expensive equipment such as a thermocycler. Because this test is rapid, cost efficient, labor efficient, accurate, and simple to run and read, it may be readily incorporated into portable point-of-care formats. These attributes make it ideally suited for use in locations where Loa loa infection is endemic. These advantages may lead to this technology becoming the new standard for diagnosis of Loa loa infections and a valuable tool, in control programs, to identify risks for adverse treatment reactions. CRADA Opportunity: The National Institute of Allergy and Infectious Disease (NIAID) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Rapid Molecular Assays for Specific Detection and Quantitation of Loa Loa Microfilaremia. For collaboration opportunities, please contact Johanna Schneider, Ph.D. at Schneiderjs@niaid.nih.gov or 301-451-9824.

Humanized Monoclonal Antibodies Efficient for Neutralization of Tick-Borne Encephalitis Virus (TBEV)

Thu, 29 Sep 2011 21:00:00 GMT

TBEV causes serious illnesses from meningitis to meningo-encephalitis, totaling 3,000 cases of hospitalization in Europe and between 5,000-10,000 cases in Russia reported every year. The Far Eastern hemorrhagic TBEV strains are associated with a mortality rate (between 1-2%), higher than other strains isolated in the Siberia or Western Europe. There is a high proportion (up to 46%) of TBEV patients with temporary or permanent neurological sequelae. The number of TBEV infections has increased steadily and TBEV cases have been reported in new areas, probably reflecting an increased spread of vector tick species. Prevention of TBEV infections has been carried out in a few countries in Europe by immunization using an inactivated TBEV vaccine. The vaccine carries a high manufacturing cost and requires a regimen of multiple doses, and for this reason, vaccination is not generally carried out. The materials disclosed are humanized monoclonal antibodies derived from TBEV-neutralizing Fab antibodies isolated from infected chimpanzees by repertoire cloning. One antibody in particular, MAb 2E6, has been demonstrated to bind to and neutralize a TBEV/dengue type 4 virus chimera (via interaction with the TBEV antigenic determinants) as well as the related Langat virus. Protection against TBEV/DEN-4 infection and Langat infection has been demonstrated using animal models of infection. The antibodies disclosed, in particular MAb 2E6, have the potential for use as prophylactic and therapeutic agents against TBEV and Langat virus. Additionally, these antibodies may be suitable as diagnostic reagents for the detection of TBEV and/or Langat virus. CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize TBEV monoclonal antibodies. For collaboration opportunities, please contact Wade Williams at 301-827-0258.

Pharmaceutical Compounds for the Treatment of Spinal Muscular Atrophy and Other Uses

Wed, 21 Sep 2011 01:00:00 GMT

The SMA Project (http://www.smaproject.org/programs.html) was established by NINDS to identify new compounds with improved effectiveness, safety, and pharmacokinetic characteristics aimed at finding a new therapeutic treatment for Spinal Muscular Atrophy (SMA), a paralyzing and often fatal disease of infants and children. The result of the SMA Project medicinal chemistry optimization effort is a library of ~1400 indoprofren analogues with drug like properties. A lead pre-clinical candidate for SMA has been identified based on several factors, including its ability to increase SMN expression.

The mechanism by which these compounds affect ribosomal fidelity proves to be useful for many genetic CNS diseases. The ability of these compounds to read through nonsense stop codons, coupled with the ability to cross the blood-brain barrier and drug like properties, makes these compounds attractive as therapeutics for diseases such as Muscular Dystrophy and Cystic Fibrosis. Preliminary results in HIV and HPV assays show that these compounds potently inhibit viral replication, presumably via inducing ribosomal frame shift, suggesting potential for antiviral therapy. In addition, these compounds have been shown to be non-toxic and well-tolerated at high doses in rodents. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize treatment for SMA. For collaboration opportunities, please contact Melissa Maderia at maderiam@mail.nih.gov.

A Novel Optomechanical Module that Enables a Conventional inverted Microscope to Provide Selective Plane Illumination Microscopy (iSPIM)

Tue, 30 Aug 2011 05:00:00 GMT

The invention describes an optomechanical module that, when engaged with a conventional inverted microscope, provides selective plane illumination microscopy (iSPIM). The module is coupled to the translational base of the microscope whereby a SPIM excitation objective is engaged to one portion of the mount body, and a SPIM detection objective (having a longitudinal axis perpendicular to that of the excitation objective) is engaged to another portion of the mount body. Such a system offers the advantages of SPIM (optically sectioned, high-speed volumetric interrogation of living samples, enabling, for example, the study of developmental or neuronal dynamics at high frame rates), while maintaining the flexibility and sample geometry of commercially available inverted microscopes (thus additionally allowing wide-field, TIRF, confocal, or 2 photon imaging of samples). CRADA Opportunity: The NIBIB is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize applications of the invention. For collaboration opportunities, please contact Hari Shroff at 301-435-1995 or hari.shroff@nih.gov.

Vaccine to Prevent BK Polyomavirus-associated Kidney and Bladder Infections in Organ Transplant Recipients

Tue, 30 Aug 2011 09:00:00 GMT

Nearly all adults have chronic urinary tract infections with one or more strains of BK polyomavirus (BKV). In healthy persons, the infection is controlled by the immune system and no symptoms are apparent. However, immunosuppressed persons, such as organ transplant recipients, can suffer from bladder disease or kidney disease caused by uncontrolled BKV growth. BKV causes cancer in animals; it is unknown if the same is true in humans. A significant need remains for a means of preventing BKV infection and associated pathologies.

Researchers at the National Cancer Institute, NIH, have developed compositions and therapeutic methods for pre-vaccination of organ transplant recipients against BKV and prognostic methods to identify patients that may benefit from the vaccination. Methods for producing a BKV vaccine against all four known BKV serotypes are in development. CRADA Opportunity: The NCI Center for Cancer Research, Laboratory of Cellular Oncology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

Human Monoclonal Antibodies Cross-reacting to Insulin-like Growth Factors IGF-I and IGF-II as Potential Anti-tumor Agents

Tue, 30 Aug 2011 13:00:00 GMT

The type 1 insulin-like growth factor (IGF) receptor (IGF1R) is over-expressed by many tumors and mediates proliferation, motility, and protection from apoptosis. Agents that inhibit IGF1R expression or function can potentially block tumor growth and metastasis. Its major ligands, IGF-I, and IGF-II are over-expressed by multiple tumor types. Previous studies indicate that inhibition of IGF-I, and/or IGF-II binding to its cognizant receptor negatively modulates signal transduction through the IGF pathway and concomitant cell proliferation and growth. Therefore, use of humanized or fully human antibodies against IGFs represents a valid approach to inhibit tumor growth.

The present invention discloses the identification and characterization of a fully human monoclonal antibody designated m708.5 that has been affinity maturated against IGF-I and IGF-II and displays extremely high affinities for IGF-I and IGF-II in the picoM range. The m708.5 antibody potently inhibited signal transduction mediated by the IGF-1R interaction with IGF-I and IGF-II and blocked phosphorylation of IGF-IR and the insulin receptor. Further, this antibody inhibited migration in the MCF-7 breast cancer cell line at the picoM range. Therefore, this antibody can be used to prevent binding of IGF-I and/or IGF-II to its concomitant receptor IGFIR, consequently, modulating diseases such as cancer. CRADA Opportunity: The NCI CCR Nanobiology Program, Protein Interaction Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

TL1A Transgenic Mice for the Study of Inflammatory Bowel Disease (IBD) and Allergic-Type Immune Responses

Tue, 30 Aug 2011 17:00:00 GMT

TL1A is a TNF family cytokine that co-stimulates T-cell proliferation and cytokine production through its interactions with the TNF family receptor DR3. TL1A-DR3 interactions have been shown to be important for the development of autoimmune inflammatory diseases, including inflammatory bowel disease (IBD).

In order to probe the role of TL1A-DR3 interactions in IBD, NIAMS inventors have developed transgenic mice that constitutively express TL1A in T cells or in dendritic cells. These mice spontaneously develop inflammatory small bowel pathology that is IL-13 dependent, and that closely resembles intestinal responses to allergens and to nematode infection.

These mice represent a unique model for the study of IBD, and in particular, the role of IL-13 in the development of this disease. They may also be used as a platform for investigating agents that block TL1A-DR3 interactions and the pathology associated with chronic TL1A expression. CRADA Opportunity: The National Institute of Arthritis and Musculoskeletal and Skin Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize TL1A Transgenic Mice. For collaboration opportunities, please contact Cecilia Pazman at pazmance@mail.nih.gov.

Methods of Treating Giardiasis Using FDA-Approved Compounds

Fri, 12 Aug 2011 21:00:00 GMT

This technology includes a group of at least twenty-nine, diverse, commercially available compounds that are newly identified for activity against Giardia lamblia parasites. At least six of the candidate compounds, Bortezomib, Decitabine, Hydroxocobalamin, Amlexanox, Idarubicin, and Auranofin have preexisting FDA approval for human use for other (non-Giardia) conditions. Another three compounds, Fumagillin, Nitarsone and Carbadox have preexisting approval for veterinary use for non-Giardia conditions. Additional active compounds identified include: Acivicin, Riboflavin butyrate, BTO-1, GW9662, Dinitroph-dfgp, Deserpidine, Tetramethylthiuram disulsulfide, Disulfiram, Mitoxantrone, Ecteinascidin 743, 17-allyaminogeldanamycin, Carboquone and Nocodazole. The anti-Giardial activity of these compounds presents a cost saving opportunity for the rapid development of new, better tolerated treatments for the most prevalent human intestinal parasite infection in the United States and the world. CRADA Opportunity: The NHGRI is seeking stateents of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Novel Compounds for Treatment of Giardiasis. For collaboration opportunities, please contact Claire Driscoll, NHGRI, at cdriscol@mail.nih.gov.

An Automated Method for Precise Measurement of Vertebral Body Height and Intervertebral Disk Height Using Computed Tomography

Sat, 13 Aug 2011 01:00:00 GMT

Vertebral fractures due to osteoporosis result in loss of vertebral height. Degenerative disk disease in the spine results in loss of disk height. Currently, radiography and magnetic resonance imaging are used to assess vertebral and disk height, and measurements are done manually. The present invention offers improved method to measure vertebral and disk heights. The invention provides computer algorithm that substantially automates the task, and uses computed tomography. The advantage of computed tomography over radiography is that of 3D imaging over 2D imaging. Computed tomography's advantage over MRI is better image resolution. The combination of automation and superior imaging capability makes the method substantially more precise than previous ones. This allows better detection of changes in vertebral height and disk height over time, and thus aids in the planning of appropriate medical treatment in cases associated with the loss of vertebral or disc heights, such as in osteoporosis for example. CRADA Opportunity: The National Institute of Arthritis and Musculoskeletal and Skin Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact Brian W. Bailey, Ph.D. at bbailey@mail.nih.gov.

Quantitative Measurement of Syndesmophytes in Ankylosing Spondylitis Using Computed Tomography (CT)

Fri, 12 Aug 2011 05:00:00 GMT

Syndesmophyte (abnormal bone) growth in the spine is a hallmark of Ankylosing Spondylitis, a type of inflammatory arthritis. Syndesmophyte growth is currently monitored using semi-quantitative scoring of radiographs, but radiographs consider only a small part of the vertebra, and the method is subject to reader error. Because syndesmophytes grow slowly, radiographs also lack sensitivity. The invention provides a method to measure syndesmophytes using data from computed tomography scans of the lumbar spine. It provides computer algorithm that fully quantitates syndesmophyte volumes in three-dimension space. This method allows precise and accurate measurement of the presence and rate of growth of syndesmophytes over time, which for the first time will permit testing of whether any treatments can slow the progression of this type of spinal arthritis. CRADA Opportunity: The National Institute of Arthritis and Musculoskeletal and Skin Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this technology. For collaboration opportunities, please contact Brian W. Bailey, Ph.D. at bbailey@mail.nih.gov.

Tumor Markers for Potentially Predicting Outcome of Anti-angiogenesis Therapy

Fri, 05 Aug 2011 09:00:00 GMT

During the past decade, anti-angiogenesis therapy has evolved as a promising approach to the treatment of cancer. However, a significant fraction of patients do not benefit from anti-angiogenesis therapy, either by itself or in combination with chemotherapy. A significant need remains for a means of predicting clinical benefit from anti-angiogenesis therapy.

Researchers at the National Cancer Institute, NIH, have identified tumor cell apoptosis, p53, and HER2 as having potential predictive significance for treatment outcome in breast cancer patients who received anti-angiogenesis therapy in combination with chemotherapy. The researchers have developed a quantitative antibody-based testing method for correlating expression of p53 and HER2 and tumor apoptosis with clinical outcome. These markers can be potentially applied to predict which patients should receive anti-angiogenesis therapy plus chemotherapy. CRADA Opportunity: The National Clinical Target Validation Laboratory, DCTD, NCI, NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize p53, tumor apoptosis, and HER2 as markers for anti-angiogenesis therapy. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

An In-Vitro Cell System Useful For Identification of RORgamma Antagonists

Wed, 27 Jul 2011 13:00:00 GMT

The retinoid-related orphan receptors alpha, beta and gamma (RORalpha, beta and gamma , also referred to as NR1F1, 2 and 3, respectively) comprise a distinct subfamily of nuclear receptors. Study of ROR-deficient mice has implicated RORs in the regulation of a number of biological processes and revealed potential roles for these proteins in several pathologies. NIH investigators have developed an in-vitro system using CHO cells stably expressing a TET-On expression vector regulating RORgamma and a RORE-Luciferase reporter. This system allows inducible expression of RORgamma upon addition of doxycycline. Upon its induction RORgamma binds to the RORE in the luciferase reporter plasmid and induces luciferase. This system can be used to identify RORgamma antagonists. This system has been tested successfully in 1536-well plate high throughput analysis. CRADA Opportunity: The NIEHS, Laboratory of Respiratory Biology, Cell Biology Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize retinoid-related orphan receptors (RORs) function in chronic diseases. For collaboration opportunities, please contact Elizabeth M. Denholm, Ph.D. at denholme@niehs.nih.gov.

Pertussis Vaccine

Tue, 26 Jul 2011 17:00:00 GMT

Despite mass vaccination, reported pertussis cases have increased in the United States and other parts of the world, probably because of increased awareness, improved diagnostic means, and waning vaccine-induced immunity among adolescents and adults. Licensed vaccines do not kill the organism directly; the addition of a component inducing bactericidal antibodies would improve vaccine efficacy. This application claims Bordetella pertussis and Bordetella bronchiseptica LPS-derived core oligosaccharide (OS) protein conjugates. B. pertussis and B. bronchiseptica core OS were bound to aminooxylated BSA via their terminal Kdo residues. The two conjugates induced similar anti-B. pertussis LPS IgG levels in mice. Conjugate-induced antisera were bactericidal against B. pertussis. CRADA Opportunity: The NICHD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize vaccines against pertussis. For collaboration opportunities, please contact Joseph Conrad, III, Ph.D. at jmconrad@mail.nih.gov. Click here to view the NICHD collaborative opportunity announcement.

Layered Electrophoretic Transfer for Analysis of Low or Medium Abundant Proteins in Tissue Samples

Tue, 26 Jul 2011 21:00:00 GMT

The subject invention is a method to selectively process the protein content from a two dimensional sample, such as a tissue section, for more detailed analysis. It is particularly useful for analysis of a subset of proteins from a complex protein mixture. The method employs a layer of polyacrylamide gels and an electric field. Proteins from the sample are transferred and sieved through a stack of polyacrylamide gels of varying concentrations. Thus, it is possible to analyze specific subsets of proteins in the different gel layers and maintain the two dimensional location of the proteins within the original sample. One of the advantages of this technology is that it allows for isolation and subsequent analysis of low abundant or medium abundant proteins by a number of different methodologies such as imaging mass spectrometry. CRADA Opportunity: The Center for Cancer Research, Laboratory of Pathology, Pathogenetics Unit, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize layered electrophoretic transfer (LET). Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Oral Vaccine for Inducing Mucosal Immunity

Fri, 22 Jul 2011 01:00:00 GMT

Available for licensing is a micro/nanoparticle oral vaccine delivery system that specifically targets the large intestine for vaccine deposition and in situ immune activation, with minimal perturbation in the upper part of the gastrointestinal (GI) tract.

Vaccine delivery to the large intestine has been experimentally demonstrated as an effective means for inducing mucosal immunity against infections transmitted through the recto-genital mucosal area such as sexually transmitted disease as well as fungal and parasitic infections. In this system, the vaccine components are encapsulated by nanometer-sized particles to allow optimal uptake once it reaches the lumen and makes contact with the intestinal mucosal surface. To protect from premature degradation and uptake in the upper GI, these particles are coated within micrometer-sized particles. This coating is designed with a pH- and time-dependent release profile that is optimized for vaccine uptake to occur within the large intestine. This particular feature may also make this technology a potential delivery system for recto-colon cancer therapies. CRADA Opportunity: The Center for Cancer Research, Vaccine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Oral Delivery of a Vaccine to the Large Intestine to Induce Mucosal Immunity. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Monoclonal Antibodies for Rare Diseases

Thu, 21 Jul 2011 05:00:00 GMT

Available for licensing are three monoclonal antibodies (mAb) that bind with high specificity and affinity to the tumor cell surface antigen tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 is expressed in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), two incurable B-cell malignancies that are designated as rare diseases by NIH’s Office of Rare Diseases Research. Therapeutics for rare diseases can qualify for orphan drug status and receive expedited review by the FDA. Currently, there are no therapeutic mAbs that target CLL or MCL but not healthy cells.

Investigators from the National Cancer Institute developed chimeric antibodies that selectively target ROR1 malignant B-cells but not normal B-cells. Additionally, this technology allows for mAb derivatives with potentially higher pharmacokinetic and/or pharmacodynamic activity, including humanized mAb in an IgG and IgM format, antibody-drug conjugates, immunotoxins, and bispecific antibodies. These three mAbs have been characterized in vitro for mediating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, apoptosis, and internalization. Results show that these mAbs bind with high specificity and affinity to three different epitopes on human ROR1, and ROR1-expressing primary CLL cells from untreated CLL patients and MCL cell lines. Moreover, as these antibodies selectively target ROR1, they can also be used to diagnose B-cell malignancies. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Experimental Transplantation and Immunology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-ROR1 monoclonal antibodies and their derivatives. Please contact Dr. Christoph Rader at (301) 451-2235 or raderc@mail.nih.gov for more information.

An Antibody Specific for the Ubl4A Protein

Thu, 21 Jul 2011 09:00:00 GMT

The antibody developed against the Ubl4A protein is available for licensing. Ubl4A is involved in the proper targeting of tail-anchored proteins to membranes by acting as a chaperone to prevent inappropriate interactions or aggregation. Alterations in membrane insertion or protein degradation may be related to Ubl4a in certain disease states making Ubl4a an attractive biomarker for the study of disease development or as a tool for the development of assays for disease detection. CRADA Opportunity: The NICHD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Ubl4A assay detection for disease diagnostics. Please contact Charlotte McGuinness at 301-435-3130 or mcguinnc@mail.nih.gov for more information.

Immunocompetent Mouse Model for Tracking Cancer Progression

Fri, 01 Jul 2011 13:00:00 GMT

The technology is a transgenic mouse model tolerized to firefly Luciferase (ffLuc)- and enhanced green fluorescent protein (eGFP)-labeled tissue whilst maintaining normal immune function. Luc and eGFP are the most frequently used bioimaging markers to track cancer progression in pre-clinical mouse models. As these markers are immunogenic, their reporter activity becomes diminished over time and so their use has largely been limited to immunodeficient mice. However, immune function is crucial for tumor development and progression, making the use of immunocompetent mice more desirable.

The immunocompetent mouse model described in this invention was generated using the rat growth hormone gene promoter (rGH) to target ffLuc-eGFP fusion gene expression to the pituitary gland, restricting any resulting interfering reporter signal within the head. This allows the tracking of cancer progression throughout the body, where the reporter activity of introduced ffLuc/eGFP-labeled tumors is maintained, despite normal immune function. These immunocompetent rGH-ffLuc-eGFP transgenic mice can be used as hosts in cancer models, allowing long-term in vivo monitoring of the progression of ffLuc/eGFP-labeled tumor cells in the body, which may lead to more clinically relevant insights into cancer progression, metastases and response to therapies. CRADA Opportunity: The National Cancer Institute Center for Cancer Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize immunocompetent rGH-ffLuc-eGFP transgenic mice. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Breakthrough Immunotherapy for Brain Cancer: Epidermal Growth Factor Receptor Variant III Chimeric Antigen Receptors

Fri, 01 Jul 2011 17:00:00 GMT

Scientists at the National Institutes of Health (NIH) have developed chimeric antigen receptors (CARs) with high affinity for the epidermal growth factor receptor variant III (EGFRvIII) to use as a promising immunotherapy for aggressive brain cancer (glioblastoma) as well as several other malignancies. CARs are hybrid proteins consisting of the portion of an antibody that recognizes a cancer antigen, in this case human monoclonal antibody 139 which recognizes EGFRvIII, fused to protein signaling domains that serve to activate the CAR-expressing cell. Human cells that express CARs, most notably T cells, can recognize specific tumor antigens in an MHC-unrestricted manner with high reactivity and mediate an immune response that promotes robust tumor cell elimination. CRADA Opportunity: The National Cancer Institute, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cell-based immunotherapies targeting EGFRvIII expressing cancers. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Inhibitors of Human Apurinic/apyrimidinic Endonuclease 1 (APE1), an Anticancer Drug Target

Fri, 01 Jul 2011 21:00:00 GMT

APE1 is the primary mammalian enzyme responsible for the removal of abasic (AP sites) in DNA and functions as part of the base excision DNA repair pathway (BER). BER is instrumental in the repair of DNA damage caused by DNA alkylating agents (e.g. many cancer chemotherapeutics). APE1 has been shown to be overexpressed in cancer cells. It has been postulated that APE1 would be an attractive target in anti-cancer treatment paradigms; preclinical and clinical data confirm that APE1 is a valid anticancer drug target.

To date, only one APE1 small molecule inhibitor has progressed to clinical trials (methoxyamine hydrochloride), and this compound inhibits a wide range of repair processes, which could result in undesired side-effects. The NIH inventors now report the discovery of a novel APE1 small molecule inhibitor, which exhibits potent in vitro activity, potentiates the cytotoxicity of DNA damaging agents (alkylators methylmethane sulfonate and Temozolomide), results in the accumulation of AP sites, and has favorable pharmacokinetic properties. The inventors plan to carry out further studies in mouse tumor xenograft models. CRADA Opportunity: The NIH Center for Translational Therapeutics, NHGRI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the above technology. Please contact Lili Portilla, Acting Director of Technology Transfer and Partnerships, NCTT at Lilip@nih.gov for more information.

Mouse Model and Derived Cells That Hypersecrete Leukemia Inhibitory Factor (LIF)

Sat, 02 Jul 2011 01:00:00 GMT

Embryonic stem cells (ESCs) are pluripotent cells that can be cultured indefinitely, and maintain their capability to differentiate into all cell lineages. To maintain these cells as well as various types of related induced stem cells and progenitor cells in culture, Mouse Embryonic Fibroblasts (MEFs) are routinely used as feeder cells, largely to serve as a source of Leukemia Inhibitory Factor (LIF). ESCs can also be cultured without feeders if the medium is supplemented with recombinant LIF and other factors. However, these methods of culturing ESCs suffer from certain drawbacks, such as limited proliferation capacity and variability of primary MEFs. Therefore, finding improved conditions that maintain ESC pluripotency is an area of great interest.

Scientists at NIEHS have now developed a knock-in (KI) mouse model in which LIF is overproduced from its endogenous locus because of increased stability of its mRNA. MEFs and presumably other cells derived from the homozygous mice hypersecrete LIF protein; lesser degrees of overexpression would be expected from heterozygous mice. These mice can be used to study LIF function, including how LIF contributes to various physiological and pathological states. Cells derived from these mice can be used to culture ESCs, as well as other progenitor cells. Cells or genetic material derived from these mice can also be used as sources of LIF for isolation and purification. CRADA Opportunity: The NIEHS Laboratory of Signal Transduction is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these mice or other strains derived from them, or cells or other reagents derived from them. Please contact Dr. Elizabeth Denholm (denholme@niehs.nih.gov) in the NIEHS Office of Technology Transfer, or the Inventor Dr. Perry Blackshear (black009@niehs.nih.gov) for more information.

System for Correction of MRI Head Motion

Sun, 26 Jun 2011 05:00:00 GMT

Motion artifacts continue to be a significant problem in MRI of human brain. Prospective motion correction based on external tracking systems has been proposed to ameliorate this issue. However, the calibration of these systems is very complicated and time consuming, as it requires a camera system calibration as well as a calibration between camera and MRI system using dedicated phantoms. An alternative motion correction method for MRI that does not require calibration and can work with just a single video camera has been developed and is available for licensing. This technology can be broadly applied in MRI to account for motion artifacts in order to improve acquisition time and provide enhanced resolution. This technique will provide a needed method to obtain reliable MRI scans for uncooperative patients (children, seizure patients, etc.) without the need and expense of multiple scans. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke - Advanced MRI Section - Laboratory of Functional and Molecular Imaging is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize MRI methods to improve data collection by improved homogeneity, resolution, etc. Please contact Dr. Melissa Maderia at 301-451-3943 or maderiam@mail.nih.gov for more information.

Antibody and Immunotoxin Treatments for Mesothelin-expressing Cancers

Fri, 17 Jun 2011 09:00:00 GMT

Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer and pancreatic cancer. As a result, mesothelin is an excellent candidate for tumor targeted immunotherapeutics. However, the antibodies against mesothelin that are available for clinical trials are of murine origin. These antibodies have the potential to elicit immune responses in patients, which may adversely affect the ability to provide patients with repeated doses. Thus, the clinical application of the antibodies may be limited.

In order to address the issue of immunogenicity in patients, NIH inventors have generated anti-mesothelin antibody variable fragments (Fv) of human origin. These antibody fragments (HN1 and HN2) have the ability to efficiently recognize mesothelin on the surface of numerous cancer cells. As a result, these antibody fragments represent an attractive therapeutic alternative to the murine anti-mesothelin antibodies currently being tested in clinical trials. CRADA Opportunity: The National Cancer Institute Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antibody-based treatments of mesothelin-expressing cancers. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Increased Therapeutic Effectiveness of Immunotoxins Through the Use of Less Immunogenic Toxin Domains

Wed, 15 Jun 2011 13:00:00 GMT

Targeted toxins (e.g., immunotoxins) are therapeutics that have at least two important components: (1) a toxin domain that is capable of killing cells and (2) a targeting domain that is capable of selectively localizing the toxic domain to only those cells which should be killed. By selecting a targeting domain that binds only to certain diseased cells (e.g., a cell which only expresses a cell surface receptor when in a diseased state), targeted toxins can kill the diseased cells while allowing healthy, essential cells to survive. As a result, patients receiving a targeted toxin are less likely to experience the deleterious side-effects associated with non-discriminate therapies such as chemotherapy or radiation therapy.

A particular toxin that has been used in targeted toxins is Pseudomonas exotoxin A (PE). The effectiveness of PE-containing targeted toxins has been demonstrated against various forms of cancer, including hairy cell leukemia (HCL) and pediatric acute lymphocytic leukemia (pALL). Although early variations these targeted toxins have demonstrated efficacy upon first administration, the continued administration of a targeted toxin often leads to a reduced patient response. The primary cause of the reduced response is the formation of neutralizing antibodies against PE by the patient.

Several variations of PE have been created to reduce the immunogenicity of PE as a means of increasing the therapeutic effectiveness of targeted toxins through multiple rounds of drug administration. This technology involves the identification of two important B-cell epitopes on PE, and the elimination of those epitopes by mutation. These new PE variants retain a sufficient cell killing activity while increasing their therapeutic effectiveness toward patients that receive multiple administrations. By further combining these new mutations with previously identified modifications that also improve the efficacy of PE-based targeted toxins, it may be possible to treat any disease characterized by cells that express a particular cell surface receptor when in a disease state. CRADA Opportunity: The National Cancer Institute, Molecular Biology Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Mouse Xenograft Model for Mesothelioma

Wed, 15 Jun 2011 17:00:00 GMT

Malignant mesothelioma is a cancer that presents itself in the protective lining of several organs (e.g., lung, heart, testis, etc.). The primary cause for mesothelioma is direct or indirect exposure to asbestos, although the disease can present without any prior exposure. Mesothelioma is relatively rare, but the prognosis for patients is poor, indicating a need to better understand and treat the disease. Current treatments often involve chemotherapy and radiation therapy, although recent studies have employed the use of therapeutic antibodies and antibody-targeted toxins.

This invention involves the creation of a new mouse model for mesothelioma. By creating xenografts with mesothelioma cells that express GFP-Luciferase fusion proteins, the xenografts can be detected to a high degree of sensitivity, and monitored for several months following implantation. The high level of detection sensitivity improves the ability to monitor disease progression in response to therapeutic candidates, thereby allowing more efficient drug screening and evaluation. This has already been demonstrated by using the mouse to evaluate an anti-mesothelioma immunotoxin known as SS1P, a drug candidate that is currently being evaluated for clinical effectiveness. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize monoclonal antibodies and immunoconjugates targeting malignant mesotheliomas. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Monoclonal Antibodies to Glypican-3 Protein and Heparin Sulfate for Treatment of Cancer

Wed, 15 Jun 2011 21:00:00 GMT

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and is among the more deadly cancers in the world due to its late detection and poor prognosis. HCC is often associated with liver disease, curtailing traditional chemotherapy as a treatment option. While surgical resection offers the best method for long term treatment of the disease, only a small portion of HCC patients are eligible for this procedure. As a result, there is a need for new treatments that can be successfully applied to a large population of HCC patients.

Glypican-3 (GPC3) is a cell surface protein that is preferentially expressed on HCC cells. Evidence has demonstrated that a soluble form of GPC3 that is incapable of cell signaling has the ability to inhibit the growth of HCC cells. This suggested that blocking GPC3 signaling could serve as a therapeutic approach for treating HCC.

This invention concerns monoclonal antibodies against GPC3 and their use, either by themselves or as the targeting domain for an immunotoxin, for the treatment of GPC3-expressing cancers such as HCC. Specifically, the inventors have generated two distinct monoclonal antibodies to GPC3. The first monoclonal antibody (HN3) binds to a conformational epitope on the cell surface domain of GPC3. The second monoclonal antibody (HS20) binds specifically to heparin sulfate chains on GPC3.

By blocking GPC3 function, these antibodies can inhibit the growth of HCC cells, thereby decreasing the ability of tumors to grow and metastasize. Furthermore, by using the antibodies to target a toxin to only those cells that express GPC3, cancer cells can be eliminated while allowing healthy, essential cells to remain unharmed. Thus, monoclonal antibodies to GPC3 (and corresponding immunotoxins) represent a novel therapeutic candidate for treatment of HCC, as well as other cancers associated with the differential expression of GPC3. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize human monoclonal antibodies or immunoconjugates such as immunotoxins and antibody-drug conjugates against GPC3, soluble GPC3 and its immunoconjugates such as Fc fusion proteins, large scale antibody production, and HCC xenograft mouse models. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

MicroRNA-205 for the Treatment and Diagnosis of Parkinson Disease

Thu, 16 Jun 2011 01:00:00 GMT

Parkinson disease (PD) is a devastating neurodegenerative movement disorder, pathologically characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of intracytoplasmic inclusions named Lewy bodies and Lewy neurites (Schapira, Baillieres Clin. Neurol. 6:15-36, 1997). Increasing numbers of genes have been identified as a genetic cause of PD (Hardy et al., Ann. Neurol. 60:389-398, 2006), for example, multiple missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were recently found to be associated with an autosomal dominant form of familial PD (Paisan-Ruiz et al., Neuron 44:595-600, 2004; Zimprich et al., Neuron 44:601-607, 2004; Zabetian et al., Neurology 65:741-744, 2005). Recent genome-wide association studies (GWAS) also revealed LRRK2, together with SNCA (encoding alpha-syn) and PARK16, as shared risk loci for PD (Simon-Sanchez et al., Nat. Genet. 41:1308-1312, 2009; Satake et al., Nat. Genet. 41:1303-1307, 2009), indicating a potential contribution of normal LRRK2 protein to the etiology of sporadic PD cases.

Micro-RNAs (miRNAs or miRs) are evolutionarily conserved small non-protein coding transcripts that bind to partially complementary binding sites in the 3’ untranslated region (3’-UTR) of target messenger RNAs (mRNAs) and control the translation of their target mRNAs at the post-transcriptional level (Bartel, Cell 116:281-297, 2004). Several miRNAs have been associated with neurodegenerative disease as well as synaptic plasticity, memory formation and developmental cell fate decisions in the nervous system (Hebert and De Strooper, Trends Neurosci. 32:199-206, 2009; Kosik, Nat. Rev. Neurosci. 7:911-920, 2006).

NIH inventors have recently discovered that LRRK2 protein expression is significantly increased in the brain of PD patients, while expression of miR-205 is specifically down-regulated in the same patients. Also, the NIH inventors have discovered that the expression levels of LRRK2 and miR-205 are dynamically regulated and reversely correlated in multiple brain regions and at different ages in mouse brains, indicating that miR-205 plays a regulatory role in LRRK2 protein expression.

Based on these novel findings, the present technology provides for novel methods of treatment of patients suffering from PD disease by modulating the amount of miR-205 in patients by administration of a miR-205 gene product, a vector encoding a miR-205 gene product or an agent that increases expression of miR-205. The present technology also provides for methods of determining the effectiveness of different candidate drugs for the treatment of PD, methods of diagnosing PD, or having an increased susceptibility to developing PD, and an in vitro process for identifying a therapeutic agent for the treatment of PD. CRADA Opportunity: The National Institute on Aging, Transgenics Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize microRNA-205 or other reagents for the treatment and diagnosis of Parkinson Disease. Please contact Nicole Guyton, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information. Click here to view the NIA collaborative opportunity announcement.

Liver Segmental Anatomy and Analysis from Vessel and Tumor Segmentation

Wed, 15 Jun 2011 05:00:00 GMT

The invention is a novel graph-based method for the automated segmentation of tumors and major intra-hepatic blood vessels and identification of the liver anatomical segments. The method allows visualization and risk analysis for interventional planning involving the liver. The method avoids the shortcomings of the traditional graph cuts or intensity-based segmentation methods by including multi-phase enhancement modeling and shape likelihoods. The segmented vessels can be correctly classified into right, middle and left hepatic, and right and left portal veins using a hybrid process that incorporates anatomical information and competitive region growing. Tumors can be detected and segmented using their differential enhancement and shape with accuracy comparable to the reports from the Medical Image Computing and Computer Assisted Intervention (MICCAI) liver tumor segmentation competition. Furthermore, a vessel tracker allowed fitting planes to the major hepatic vasculature and identifying the liver segments according to the Couinaud atlas. The automated method can be used in conjunction with manual and automatic liver segmentations to perform enhanced visualization for diagnosis and planning of interventions. CRADA Opportunity: The NIH Clinical Center, Department of Radiology and Imaging Sciences, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize techniques for the enhanced visualization, diagnosis and image-based interventions of the liver. Please contact Ken Rose, Ph.D. at 301-435-3132 or rosek@mail.nih.gov for more information. Click here to view the NIH Clinical Center collaborative opportunity announcement.

A System for Delivering Embolic Materials Endovascularly to Patients

Wed, 15 Jun 2011 09:00:00 GMT

The Public Health Service seeks commercial entities interested in licensing patent rights that pertain to a system for delivering embolic materials endovascularly to patients. The system includes a smart catheter that provides quantitative feedback to a physician during embolotherapy. This includes a detecting portion for measuring flow velocity (e.g., Doppler tip), amount of reflux, and amount of embolic particles (e.g., embolization beads) delivered by the catheter. A graphical user interface displays the measured information in real-time. CRADA Opportunity: The NIH Clinical Center, Radiology and Imaging Sciences Department, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a catheter for quantitative feedback during embolotherapy. Please contact Ken Rose, Ph.D. at 301-435-3132 or rosek@mail.nih.gov for more information. Click here to view the NIH Clinical Center collaborative opportunity announcement.

Oligonucleotide Compounds that Enhance Immunity to Cancer and Reduce Autoimmunity

Wed, 15 Jun 2011 13:00:00 GMT

Suppressive cells, including macrophages and other myeloid-derived suppressor cells, regulatory T cells, and dendritic cells (DCs), have been attributed to tumor growth. DCs in particular are known to be associated with the induction of T cell tolerance in cancer, but molecular mechanisms that control DC dysfunction are complex and a better understanding of DC mechanisms in tumors is needed. Recently FOXO3, originally identified as a tumor suppressor, was associated with DC dysfunction. Additionally, therapeutics targeting FOXO3 are known to be effective at killing many tumors types, synergize with traditional therapies, and show efficacy against tumors that are otherwise resistant to conventional treatments.

The researchers at the NIH have demonstrated for the first time that FOXO3 expression by DC coincides with expression of suppressive genes that negatively regulate T cell function. They have also demonstrated that silencing FOXO3 simultaneously changes DC function, eliminating tolerogenicity and enhancing their immunostimulatory capacity. Specifically, the inventors have developed siRNAs or oligonucleotides that enhance an immune response and neutralize the activity of FOXO3 in DCs by converting suppressive cells into immunostimulatory cells. This novel approach could be applied to cancer vaccines, where dendritic cells could be treated with these small molecules prior to use in clinical therapies. Alternatively, small molecules that stimulate FOXO3 expression could be used for inducing immune suppression for autoimmune diseases like type I diabetes or multiple sclerosis. CRADA Opportunity: The National Cancer Institute Cancer and Inflammation Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents that both block FOXO3 function and enforce FOXO3 expression. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Polyclonal Antibodies against RGS7, a Regulator of G Protein Signaling, for Research and Diagnostic Use

Wed, 15 Jun 2011 17:00:00 GMT

Investigators at the National Institutes of Health have generated a polyclonal antibody against the Regulator of G protein Signaling Protein 7 (RGS7). The RGS7 protein regulates neuronal G protein signaling pathways and inhibits signal transduction by increasing the GTPase activity of G protein alpha. RGS7 may play an important role in synaptic vesicle exocytosis and in the rapid regulation of neuronal excitability and the cellular responses to stimulation. This polyclonal antibody was generated by using a purified fusion protein containing the regulator of guanine nucleotide-binding protein signaling (RGS) C-terminal region of bovine RGS. The antibody specifically recognizes RGS7 of mouse, rat, and human origin. The antibody is useful for studying the expression, functions, and interactions of RGS7 by Western blot and immunofluorescence analysis. CRADA Opportunity: The NIDDK Metabolic Diseases Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize polyclonal antibodies against the Regulator of G protein Signaling Protein 7 (RGS7). Please contact Anna Z. Amar at 301-451-2305 or aa54d@nih.gov for more information.

Novel Small Molecule Inhibitors for the Treatment of Huntington’s Disease

Fri, 03 Jun 2011 21:00:00 GMT

This technology is a collection of small molecules screened for their ability to prevent or reduce the cytotoxic effects of the protein, Huntingtin. Huntington's disease is a neurodegenerative disorder due to a dominantly acting expansion of a CAG trinucleotide repeat in exon 1 of the Huntington (HTT) gene resulting in production of the altered (mutant) protein Huntingtin, which has a long chain of polyglutamine (poly Q) attached to the exon 1 encoded protein sequence. Clinical and statistical analyses have shown that an increased number of poly Q repetition correlates with the probability of developing the disease, with 36 to 40 being the accepted cut off number for developing the disorder with high probability. It is known that poly Q repetitions impact the physical properties of Huntingtin and cause it to produce aggregates that precipitate and form inclusion bodies, which are toxic to the neuronal cells. The compounds of this invention have been screened multiply in a neuronal cell model of Huntington’s disease containing an HTT with an expanded repeat in exon 1 of 103 Qs for their ability to inhibit cytotoxicity and protein aggregation. CRADA Opportunity: The National Center for Translational Therapeutics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology further. Please contact Ms. Lili Portilla at Lilip@nih.gov for more information.

Synergistic Combination Agent (Ceramide and Vinca Alkaloids) for Cancer Therapy

Sat, 04 Jun 2011 01:00:00 GMT

Work by the Nanotechnology Characterization Laboratory (NCL), a joint initiative of NCI, NIST, and the FDA, has led to the discovery of a novel combination chemotherapy. This combination is shown to have synergistic effects on cytotoxicity to cancer cells in vitro, and to cause a substantial decrease in tumor growth in preclinical tumor models in vivo. Combination therapy using these agents may enhance the response rate of different cancers to these drugs and may significantly reduce side effects by permitting a lower therapeutic dose to be administered.

The instant invention relates to a novel combination of ceramide and vinca alkaloids, which synergistically decrease cancer cell growth without increasing the toxicity profile compared to the individual drugs. The drug combination has been rigorously evaluated in both in vitro and in vivo models of cancer, and a dose range-finding toxicology study has been conducted in rodents.

This combination induces cell death via a novel mechanism (induction of autophagy with simultaneous blockade of autophagy flux). This mechanism appears to impart selectivity of the therapy to cancer cells.

Available for licensing are methods to use the combination therapy for cancer treatment. CRADA Opportunity: The SAIC Frederick, Nanotechnology Characterization Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a ceramide and vinca alkaloid combination therapy for treatment of cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

HIF1alpha-Targeted Therapy for Diabetes and Obesity

Fri, 03 Jun 2011 05:00:00 GMT

This technology describes the use of hypoxia inducible factor 1 alpha (HIF1alpha) inhibitors for the reduction of body weight and treatment of diabetes.

In obesity, the rapid expansion of adipose tissue outpaces the oxygen supply, resulting in hypoxia. HIF1alpha, a transcription factor that plays an essential role in cellular and systemic responses to low oxygen levels, is activated in these tissues, and causes inflammation that has been linked to insulin resistance and other metabolic dysfunction.

To examine the role of hypoxia in obesity and insulin resistance, investigators at the National Cancer Institute disrupted the HIF1alpha gene (or its dimerization partner, the HIF1beta) in the adipose tissue of transgenic mice, and found that these mice were protected from obesity and insulin resistance when fed a high-fat (western) diet. In further experiments, administration of an HIF1alpha inhibitor to wild-type mice achieved similar reductions in fat mass and insulin resistance, as well as other indicators of metabolic disease. Thus, HIF1alpha inhibitors represent promising new leads for obesity and diabetes therapeutics. CRADA Opportunity: The Center for Cancer Research, Laboratory of Metabolism (LM), is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HIF1alpha inhibitors that can be used for the treatment of obesity and type 2 diabetes. The LM will be willing to collaborate with parties to evaluate potential inhibitors using the HIF1alpha adipose-specific knockout mice. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

X-Clometer: Optimizing Portable Radiography

Fri, 03 Jun 2011 09:00:00 GMT

The technology offered for licensing and commercial development relates to a method and apparatus that can significantly improve the diagnostic performance of portable chest (CXR) and abdominal x-rays. This device quantifies angulation of a patient to provide for a better comparison of day-to-day improvement.

The portable CXR is one of the most commonly requested diagnostic medical tests around the world. They are performed nearly daily on some of the sickest patients in hospitals. Paradoxically, it is well documented that portable radiography of the chest is inconsistent and often inadequate.

An upright projection best evaluates effusions, rules out free air, or detects air-fluid levels. Optimally, the images are obtained at similar angles each day, even if not erect, to allow accurate comparisons and assessment of change. It is well documented that portable radiography of the chest is inconsistent and often inadequate. To achieve optimal quality of the exam the technologist attempts the most upright projection; balanced with patient condition and ability to achieve this often impossible task. CRADA Opportunity: The NIH Clinical Center, Radiology and Imaging Sciences, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize X-Clometer. Please contact Ken Rose, Ph.D. at 301-435-3132 or rosek@mail.nih.gov for more information. Click here to view the NIH Clinical Center collaborative opportunity announcement.

Methods and Devices for Transcatheter Cerclage Annuloplasty

Wed, 25 May 2011 13:00:00 GMT

The invention relates to techniques and devices for cardiovascular valve repair, particularly annuloplasty techniques and devices in which tensioning elements are positioned to treat regurgitation of the mitral valve or tricuspid valve. More specifically, the technology pertains to a new device for myocardial septal traversal ("cerclage reentry") that also serves to capture (ensnare) and externalize the traversing guidewire. The focus of the invention is to avoid a phenomenon in cardiac surgery known as "trabecular entrapment." The device features an expandable and collapsible mesh deployed in the right ventricle to simplify capture of a reentering guidewire during transcatheter cerclage annuloplasty. The wire mesh exerts pressure against trabecular-papillary elements of the tricuspid valve to displace them against the right ventricular septal wall. By abutting the right ventricular reentry site of the cercalge guidewire, trabecular entrapment is avoided. The device comprises a shaft having a distal loop which provides a target in the interventrical myocardial septum through which a catheter-delivered tensioning system is guided. The loop ensnares the catheter-delivered tensioning system as it reenters the right ventricle or right atrium. The expandable and collapsible mesh is disposed within the right ventricle such that the catheter-delivered tensioning system is directed from the ventricular septum into the right ventricular cavity through only a suitable opening in the mesh and such that the catheter delivered tensioning system is captured or ensnared within the mesh opening. CRADA Opportunity: The National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Peg Koelble at koelblep@nhlbi.nih.gov for more information.

Thrombolytic Temperature-Sensitive Liposomes

Wed, 25 May 2011 17:00:00 GMT

The subject technology discloses a novel method for inducing targeted thrombolysis in blood vessels. In this technology, a thrombolytic agent is encapsulated within temperature-sensitive liposomes. This composition is administered into the patient’s blood circulation. Certain clots and vulnerable atherosclerotic processes elicit an endogenous heat that facilitates local thrombolytic drug release. The thermosensitive liposome can also be exogenously heated to at least its phase transition temperature to induce the release the thrombolytic agent from the liposome at the thrombus for targeted thrombolysis. The temperature for activated release can be varied, depending on the specific composition of the liposome. CRADA Opportunity: The NIH Clinical Center, Interventional Radiology Section & Center for Interventional Oncology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this novel approach to thrombolysis. Please contact Ken Rose, Ph.D. at 301-435-3132 or rosek@mail.nih.gov for more information. Click here to view the NIH Clinical Center collaborative opportunity announcement.

Peptide Therapeutics for Cardiac Failure

Fri, 20 May 2011 21:00:00 GMT

Available for licensing are therapeutic peptides that induce heart contractions without affecting blood pressure during cardiac failure. During cardiac failure, the heart suffers a decrease in contraction force, which weakens the heart’s ability to deliver blood. Interestingly, the failing heart also retains an ability to increase its contraction force. This represents the theoretical basis for treatment of heart failure with positive inotropic agents, which increase heart contractility. Currently available positive inotropic agents include catecholamines such as epinephrine, Milrinone, and beta-receptor agonists. However, these treatments demonstrate negative side effects including increased blood pressure as well as heart attack.

Investigators at the Eunice Kennedy Shriver National Institute of Child Health and Human Development have developed therapeutic peptides designated as Serpinin and its derivative pGlu-Serpinin. These peptides act via a signaling pathway independent from the classical receptor-mediated adrenergic pathway and as a result, they can increase heart contractility without affecting blood pressure. These peptides represent a novel pharmacological approach in the treatment of cardiac failure. CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Cellular Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of serpinin and pyroglu-serpinin in treatment of heart failure. Please contact Joseph Conrad at 301-435-3107 or jmconrad@mail.nih.gov for more information. Click here to view the NICHD collaborative opportunity announcement.

Vaccines for Protection Against Mucosatropic Infections

Sat, 21 May 2011 01:00:00 GMT

The invention offered for licensing and commercial development relates to the field of Vaccines. More specifically, the invention describes novel compositions, strategy and methods that can effectively induce local mucosal immune response (e.g. in a female genital tract that is infected with a mucosatropic pathogen), as well as systemic immune response. The method comprises administrating to the treated subject at least two (2) immunogenic compositions in a prime-boost regimen, each comprising an effective amount of an immunogen derived from the pathogen. The first composition is administered to the epithelial surface of the subject in combination with one or more agents or treatment to disrupt the epithelial surface (e.g.nonoxobol-9 or depot medroxyprogesterone acetate). The second immunogenic composition is administered systemically. The first composition is typically a papillomavirus pseudovirion (PsV) comprising a polynucleotide that encodes proteins on the mucosatropic pathogen. The PsV has shown to confer tropism for the basal epithelium and is uniquely capable of eliciting strong immune response at this environment. The immunogenic composition that is administered systemically is typically selected from one of the following groups: (a) a live attenuated virus (e.g. poxivirus) expressing a protein or proteins of the infecting pathogen, (b) a DNA vector encoding proteins of the pathogen, or (c) an immunogenic polypeptide from the pathogen. CRADA Opportunity: The Center for Cancer Research, Vaccine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Vaccines for Protection Against Mucosatropic Infections. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

A Novel Strategy for Development of an Effective HIV/AIDS Vaccine

Fri, 29 Apr 2011 05:00:00 GMT

The invention offered for licensing and commercial development relates to the field of HIV/AIDS Vaccines. More specifically, the invention describes a novel strategy that can be useful in effective vaccination and treatment of HIV/AIDS infected persons. In this strategy (called ‘trigger-and-neutralize’ strategy) the infected subject is primed with HIV trimeric gp 120 immunogen to induce the production of CD4i (CD4-induced) antibodies. The patient is then treated with a compound that stabilizes the ‘open’ conformation of the gp120 of the HIV virus, at which conformation the gp120 epitope is better exposed and effectively neutralized by the CD4i antibodies. CRADA Opportunity: The Center for Cancer Research, NCI/NIH is seeking statements of capability or interest from parties interested in collaborative research to further develop, produce, evaluate, or commercialize trimeric gp120 immunogens. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Novel Inhibitors of Thymic Stromal Lymphopoietin (TSLP) for Cancer Therapy

Thu, 14 Apr 2011 09:00:00 GMT

With estimated overall costs in the U.S. in 2006 at $206.3 billion and WHO predictions of 15 million new cases globally by 2020, the overall economic cost of cancer is staggering. There remains a significant unmet need for therapies to control the spread (metastasis) of cancers to other organs in the body. Available for licensing are compositions and methods of using antagonists of thymic stromal lymphopoietin (TSLP) to prevent cancer progression and metastasis.

TSLP, an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs, is also expressed in cancers regulating their escape (1-3). The cancer-promoting activity of TSLP primarily required signaling through the TSLP receptor on CD4+ T cells, promoting Th2-skewed immune responses and production of immunosuppressive factors such as IL-10 and IL-13. Expression of TSLP therefore may be a useful prognostic marker and its targeting could have therapeutic potential. Inactivation of TSLP expression or its receptor signaling can effectively control cancer progression and metastasis (1). CRADA Opportunity: The National Institute on Aging, Immunotherapeutics Unit, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize clinical application of TSLP in cancers. Please contact Nicole Guyton, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Altered miRNA Expression as Diagnostics and Therapeutics for Adrenocortical Carcinomas

Thu, 14 Apr 2011 13:00:00 GMT

This technology describes that altered human miRNA expression such as miRNA-483 and miRNA 100 can accurately predict if a patient's adrenal cortex tumor is benign or malignant. Adrenocortical carcinomas (ACC) are rare but aggressive cancers and typically have a poor prognosis. Currently, there are limited options for molecular diagnosis to distinguish malignant tumors from benign tumors of this type. As a result there are few treatment strategies for ACC.

Additionally, preliminary results suggest that altering the expression of this miRNA in ACC cells can effect cancer cell growth. Therefore, inhibiting a miRNA may serve as a therapeutic option for ACC. CRADA Opportunity: The Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of diagnostic miRNAs and to target these miRNAs for treatment. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

NAG-1 Transgenic Mouse Model

Thu, 14 Apr 2011 17:00:00 GMT

The nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) encodes a protein that has anti-inflammatory, proapoptotic, and antitumor properties. It plays a pivotal role in antitumorigenesis induced by chemopreventive compounds. Transgenic mice expressing human NAG-1 have been developed by the NIH investigator and collaborator.

The NAG-1 transgenic mice are shown to develop few tumors in response to carcinogenic stimuli than wild type mice. They are also leaner with less fat than their wild type counterparts. As such, these mice can be used to investigate the development of cancers, and they could be of value in studying obesity and the relationship to cancer risk, and inflammation. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Elizabeth M. Denholm, NIEHS Office of Technology Transfer, denholme@niehs.nih.gov, 919-541-0981, for more information.

Diagnostic and Prognostic Serum Biomarkers for Cancer Patients Treated with Cancer Vaccines

Tue, 29 Mar 2011 21:00:00 GMT

Although antibodies are a critical element of the immune response, the role of antibody responses in cancer vaccines is still unknown. Carbohydrate antigens, which are directly or indirectly involved in most types of cancer vaccines, are a class of antigens has been largely understudied but play a significant role in the immune response of cancer vaccines.

This invention involves the identification of serum biomarkers for cancer that target carbohydrate antigens. The biomarkers are specific sub-populations of serum antibodies present in the serum of patients that bind to various glycan and/or glycoprotein antigens, such as the Forssman antigen.

The biomarkers are useful for a) predicting a patient’s immune responses to a cancer vaccine, b) measuring the efficacy of a cancer vaccine, and c) determining the prognosis and long-term survival of cancer patients. CRADA Opportunity: The Center for Cancer Research, Chemical Biology Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-glycan serum antibodies as biomarkers for cancer or HIV vaccines and/or as prognostic biomarkers. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Superparamagnetic Nanocomplexes and Their Use as Contrast Agents in MRI

Wed, 30 Mar 2011 01:00:00 GMT

The invention offered for licensing and commercial development relates to the fields of cell therapy and tracking of such therapy by magnetic resonance imaging. More specifically the technology describes novel superparamagnetic magnetic resonance contrast agents, methods of making the agents, and methods of labeling cells with the contrast agents and imaging the labeled cells using magnetic resonance.

The self assembled agents are composed of three (3) components: Superparamagnetic iron oxide nanoparticle (e.g. F₃O₄), associated with a carbohydrate coating (e.g., a polycation (e.g., Protamine Sulfate); and a polycation (e.g., glycosaminoglycan:Heparin). Self-assembling superparamagnetic nanocomplexes made from simple commercially available chemicals such as Heparin sulfate (H), Protamine sulfate (P), and Ferumoxytol nanocomplexes (HPF nanocomplexes) can effectively label stem cells, immune cells, tumor cells, or any other therapeutically engineered cells for cellular MRI. Biological cells can be labeled with the nanocomplexes by contacting cells under conditions sufficient to produce the nanocomplexes, or by contacting the cells with pre-assembled nanocomplexes. The labeled biological cells can be transplanted into an individual, imaged by MRI and the migration pattern and/or cellular distribution pattern of the labeled biological cells in the subject can then be detected. This technique will readily facilitate the tracking of the therapeutic cells, and thus render cell-based therapy and/or tissue repair more precise, accurate and effective. CRADA Opportunity: The Clinical Center, Frank Laboratory, Radiology and Imaging Sciences, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Joseph A. Frank MS MD at 301-402-4314 or jafrank@helix.nih.gov for more information. Click here to view the Clinical Center collaborative opportunity announcement.

Modulation of Leucine-rich Repeats and Calponin Homology Domain-containing Protein 4 (Lrch4) Activity for Therapeutic Applications

Tue, 29 Mar 2011 05:00:00 GMT

NIH Inventors have recently discovered a novel Leucine-rich repeat and calponin homology domain-containing protein 4 (Lrch4) in a proteomic screen of the plasma membrane of lipopolysaccharide (LPS)-exposed macrophages. Expression data by RT-PCR revealed that all Lrch family members (1-4) are expressed in macrophages, but only Lrch4 was recruited into lipid rafts (signaling microdomains of the plasma membrane) by LPS. Lrch4 is the most highly expressed Lrch family member in mouse tissues. It is a predicted single-spanning transmembrane protein that is encoded by the Lrch4 gene in humans. The Lrch4 ectodomain is predicted to have a series of leucine-rich repeats, the motifs by which Toll like Receptors (TLR) are thought to bind microbial ligands. The human form of Lrch4 is 83% identical to murine Lrch4 and is predicted to have 680 amino acids and a molecular weight of 73 kDa.

NIH inventors have shown that Lrch4 is expressed on the plasma membrane of macrophages. They have determined that Lrch4 regulates pro-inflammatory signals (NF-kappaB activation, cytokine induction) emanating from all TLRs tested, and also regulates ligand-independent signals from MyD88. Further, LPS-induced p38, JNK, and NFkappaB activation are attenuated following Lrch4 knockdown, indicating that Lrch4 regulates upstream LPS signaling events. LPS-induced expression of the NF-kappaB-dependent cytokine TNFalpha was attenuated following Lrch4 knockdown at the level of both transcript and protein. Based on these and other findings, the inventors of this technology propose that Lrch4 may be a novel component of TLR receptor complexes and that modulation of Lrch4 activity might open up new opportunities for developing novel therapeutics for inflammatory diseases. CRADA Opportunity: The National Institute of Environmental Health Sciences (NIEHS) Laboratory of Respiratory Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Lrch4. Please contact Dr. Elizabeth M. Denholm at denholme@niehs.nih.gov for more information.

New Molecules for HIV Therapeutics: Fab, scFv, and Related Binding Molecules Specific for HIV-1 Rev

Tue, 29 Mar 2011 09:00:00 GMT

The invention offered for licensing and commercial development is in the field of HIV therapeutics. More specifically, the invention relates to methods and compositions for treating and/or inhibiting HIV infection or any other lentivirus. The invention describes the identification, though phage display, of a chimeric rabbit/human anti-Rev Fab (SJS-R1) that can inhibit polymerization of the HIV Rev protein and thus inhibit its normal function in virus replication. The Fab binds with very high affinity to a conformational epitope in the N-terminal half of HIV-1 Rev. The corresponding single chain antibody (scFv) was also prepared and characterized. Methods of making and using SJS-R1 Fab and SJS-R1 scFv, and antibodies and antibody fragments that share at least one CDR with SJS-R1 Fab, are provided. Specific described methods include methods of preventing or reversing polymerization of HIV Rev, methods of reducing infectivity of replication of a lentivirus, inhibiting Rev function in a cell infected with a lentivirus, and methods of treating a disease or symptom associated with Rev expression in an animal. CRADA Opportunity: The National Institute of Arthritis and Musculoskeletal and Skin Diseases, Protein Expression Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the technology. Please contact Cecilia Pazman, Ph.D. at 301-402-5579 for more information.

Agonistic Human Monoclonal Antibodies Against DR4

Tue, 15 Mar 2011 13:00:00 GMT

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its functional receptors, DR4 and DR5, have been recognized as promising targets for cancer treatment. Therapeutics targeting TRAIL and its receptors are not only effective in killing many types of tumors but they also synergize with traditional therapies, and show efficacy against tumors that are otherwise resistant to conventional treatments.

The researchers at the NIH have developed two human monoclonal antibodies (mAbs) that bind to death receptor 4 (“DR4”). One of the mAbs is agonistic and inhibits the growth of ST486 cells with IC50 of about 10nM. The two mAbs were selected from a human phage-displayed Fab library by panning against a recombinant DR4 extracellular domain. Therefore the two mAbs are fully human. These antibodies could have considerable potential as cancer therapeutics alone or in combination with other drugs. Further, these antibodies could be used as a research tool for the study of DR4. CRADA Opportunity: The National Cancer Institute, Membrane Structure and Function Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize topic of invention or related laboratory interests. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

UOK 268 Cell Line for Hereditary Leiomyomatosis and Renal Cell Carcinoma

Tue, 15 Mar 2011 17:00:00 GMT

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is an extremely aggressive cancer syndrome with no effective treatment regimen and currently no cure. The progress of identifying HLRCC treatments and cures has likely been hindered due to the lack of an HLRCC model for studying the cancer syndrome and for screening therapeutic drug candidates.

This technology describes the UOK 268 cell line, a spontaneously immortalized renal tumor cell line that may be of great interest to industry for studying HLRCC, drug screening, and searching for tumor markers related to diagnosis, prognosis, and drug resistance. This cell line is only the second spontaneously immortalized cancer cell line of its kind in the world and is unique in that it is a primary tumor cell model (the other cell line, UOK 262, is from a metastasis cell model). The UOK 268 cell line is an established, clonal, immortalized renal cancer cell line derived from the long-term culture of aggressive tumor tissues of HLRCC in a specially designed culture medium under strict culture conditions. The UOK 268 exhibits an array of HLRCC kidney cancer characteristics that can promote protein and fatty acid biosynthesis and modulate HIF activities in a manner conducive to cancer cell proliferation.

Benefits:

This is only one of two immortalized HLRCC cell lines, and is unique in that it is from a primary tumor cell model.
Developing a diagnostic to search for tumor targets and screen for HLRCC and related cancers drug candidates will have significant benefits, including early detection and treatment.

CRADA Opportunity: The Center for Cancer Research, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize UOK268 as human HLRCC primary cell line model to comparing previously established UOK262, which was from metastasis lympho node. UOK 268 is a unique cell model for studying the underlying molecular derangements associated with impaired oxidative phosphorylation in cancer and for evaluating novel therapeutic approaches for this HLRCC-associated kidney cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Therapeutic Approach to Neurodegenerative Disorders Using a TFP5-Peptide

Tue, 15 Mar 2011 21:00:00 GMT

This invention discloses methods for treating neurodegenerative diseases by administering cyclin dependent kinase 5 (Cdk5) inhibitory peptides derived from P35, the activator of Cdk5. Abnormally hyperactive Cdk5 has been shown to be associated with a variety of neurodegenerative disorders. Disclosed in this invention are isolated peptide fragments, pharmaceutical compositions and methods for use of such for treating subjects with a neurodegenerative disease, such as Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease (PD). An inhibitory fragment, TFP5, disclosed in this invention, has been shown to ameliorate symptoms of AD in disease animal models without any evidence of toxicity. In particular, TFP5 treatment of rat cortical neurons reduced hyperactivation of Cdk5 upon neuronal stress and insults. Following intraperitoneal (ip) injection, TFP5 was capable of crossing the BBB and localizing within the brain where it was found to rescue memory deficits and pathology in a double transgenic mouse (APP/PS1) AD model. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke, Neuronal Cytoskeletal Protein Regulation Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize topic of invention or related laboratory interests. Please contact Heather Gunas, J.D., M.P.H., at 301-451-3944 or gunash@mail.nih.gov for more information.

Tiopronin Specifically Kills and Re-sensitizes Multi-Drug Resistant Cells to Chemotherapy

Wed, 16 Mar 2011 01:00:00 GMT

One of the major hindrances to successful cancer chemotherapy is the development of multi-drug resistance (MDR) in cancer cells. MDR is frequently caused by the increased expression or activity of ABC transporter proteins in response to the toxic agents used in chemotherapy. The increased expression or activity of the ABC transporter proteins causes the toxic agents to be removed from cells before they can kill the cell. As a result, research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters, thus causing the chemotherapeutic agents to remain in the cell long enough to exert their effects. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects due to the inhibition of ABC transporter function in normal cells, thereby restricting their usefulness as therapeutics.

Investigators at the NIH have now discovered that the amino acid analog Tiopronin has the ability to kill multi-drug resistant cancer cells while leaving normal cells relatively unharmed. This suggests that Tiopronin can be developed as a therapeutic for multi-drug resistant cancers. Furthermore, Tiopronin re-sensitizes multi-drug resistant cells to chemotherapeutic agents over time. This may allow cyclical administration of chemotherapeutics without the development of permanent resistance to the agents, increasing the effectiveness of chemotherapy as a cancer treatment.

Importantly, Tiopronin is not an inhibitor of ABC transporter function because it kills multi-drug resistant cells without affecting the activity of ABC transporters. As a result, the undesirable side-effects that have prevented the use of inhibitors of ABC transporters as therapeutics should not affect the therapeutic application of Tiopronin. CRADA Opportunity: The National Cancer Institute, Multidrug Resistance Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Potential Chemotherapeutic Agents: Synthetic Peptide Inhibitors of the Wnt Pathway

Tue, 15 Mar 2011 05:00:00 GMT

Available for licensing are peptide inhibitors of the Wnt signaling pathway, a pathway that is activated in many cancer types. To date, there are few small molecules that target canonical Wnt/beta-catenin signaling and those that have been discovered have low potency and do not directly target beta-catenin, the pathway’s key signal mediator. The investigators have developed peptide inhibitors that selectively target a conserved region in beta-catenin essential for promoting cell growth but not cell adhesion and differentiation. Furthermore, these peptides have been synthetically modified to enhance cell penetration and structure stability thereby increasing their potency and efficacy. Interestingly, these peptides inhibit the canonical Wnt signaling pathway but not non-canonical Wnt signaling. As a result, these inhibitors potentially provide effective chemotherapies for tumors, such as colon and cervical, which depend upon canonical Wnt signaling. Moreover, as these inhibitors do not disrupt non-canonical Wnt signaling, which plays a role in kidney, lung, and vascular development, and they are likely to have minimal negative side effects. Additionally, these peptides can serve as an effective tool for researches to elucidate the roles of Wnt canonical and non-canonical signaling in development and many pathological conditions. CRADA Opportunity: The Center for Cancer Research, Cancer and Inflammation Program and Cancer and Developmental Biology Laboratory, are seeking statements of capability or interest from parties interested in collaborative research to further develop and commercialize Wnt pathway inhibitors. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Active Adaptive Detuning Systems to Improve Safety of Interventional Devices

Fri, 04 Mar 2011 10:00:00 GMT

The invention offered for licensing and commercial development is in the field of Interventional Magnetic Resonance Imaging (“iMRI”). More specifically the invention discloses interventional devices in which the heat generated at the device during the imaging process can be controlled to not exceed acceptable levels.

Active MRI compatible intravascular devices contain RF antenna to so that they are visible under MRI. However, these metallic structures may heat up significantly during interventional MRI procedures due to eddy current formation over the conductive transmission lines. The electrical field coupling between interventional devices and RF transmission coils strongly depend on the device position and orientation within the bore and insertion length of the device. Currently, conventional detuning circuit is used to decouple the conductive intravascular device during RF transmission phase of the MRI by activating the circuit with a PIN diode. However, conventional passive techniques do not adapt for each possible orientation or insertion length of the device. The current invention provides for a new active detuning system that adapts its circuit component to limit heating for every possible orientation and insertion length. The system reads out the received current signal value during RF transmission phase and changes the decoupling capacitor value by using varactor and integrated circuit components to reach new resonant condition (very high impedance). CRADA Opportunity: The National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Peg Koelble at koelblep@nhlbi.nih.gov for more information.

Single Channel MRI Guidewire

Fri, 04 Mar 2011 15:00:00 GMT

The invention offered for licensing and commercial development is in the field of Interventional Magnetic Resonance Imaging (“iMRI”). More specifically the invention discloses a guidewire for magnetic resonance imaging with a single channel design to reduce complexity and to provide conspicuous tip visibility under MRI. In the design of the present device, the guidewire body includes an antenna formed from a rod and a helical coil coupled together. The helical coil can have multiple windings without a gap between the windings. The rod passes through the windings of the helical coil and is coupled to the helical coil using a conductive joint positioned at an end of the rod and at an end of the helical coil. Insulation can be positioned between the rod and the windings of the helical coil. The configuration allows visibility of the antenna along the length of a rod, except where it enters the windings of the coil. Thus, the tip visibility is enhanced as being separated from the rod. CRADA Opportunity: The National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize technology involving single channel MRI guidewires. Please contact Peg Koelble at koelblep@nhlbi.nih.gov for more information.

System and Method for Monitoring and Controlling Radio Frequency Signals in Interventional Devices

Fri, 04 Mar 2011 20:00:00 GMT

The invention offered for licensing and commercial development is in the field of Interventional Magnetic Resonance Imaging (“iMRI”). More specifically the invention discloses interventional devices in which the heat generated at the device during the imaging process can be controlled to not exceed acceptable levels.

Interventional devices may heat up significantly during an interventional MRI procedure as a result of an RF induced current on the device. The RF induced current is caused by the coupling between the interventional device and RF electrical fields generated by the MRI. As the magnitude of the induced RF signal increases, the amount of heat that is generated also increases. The system of the present invention measures the induced RF signal and changes a decoupling capacitor value by using a varactor and a control circuit to adjust the impedance of the device and thus controls the magnitude of the RF signal. This unique design renders the device and the procedures done with it safe. CRADA Opportunity: The National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize safety interventional devices during iMRI procedures. Please contact Peg Koelble at koelblep@nhlbi.nih.gov for more information.

Method for the Detection of a Subdural Hematoma Using a Handheld Hematoma Detector and Discriminator

Sat, 05 Mar 2011 01:00:00 GMT

The invention offered for licensing and further development is a device and method for detecting hematomas. The device is based on near infrared light emitted perpendicularly into a tissue from a non-stationary emitter and on continuous detection of the reflected light with a non-stationary probe. The device is designed as a handheld detector that can be used either in an ER or at the scene of an accident, which will allow the Doctor or EMT to diagnose hematoma for patients with a Traumatic Brain Injury at the scene. Furthermore, this device can be utilized to discriminate between subdural and epidural hematoma. The invention also discloses a novel method of data analysis is. The specific combination and sequences of data analysis are performed to discriminate healthy tissue from tissue perfused with blood. In addition, an interface to a laptop will be provided that creates a 3D surface image of the location of the hematoma is displayed. This invention will result in a better triage and treatment for patients with Traumatic Brain Injury (TBI) and fills a must filled gap in TBI health care. CRADA Opportunity: The National Institute of Child Health and Human Development, Section on Biomedical Stochastic Physics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the topic of this invention or related laboratory interests. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

System and Method for Automatic Speed Adaptation Control of a Treadmill

Fri, 04 Mar 2011 06:00:00 GMT

The invention offered for further commercial development relates to the coupling of virtual reality technology with a treadmill to implement goal-oriented walking practices effectively and to promote improved learning skills during gait training. The technology will be useful in rehabilitation of individuals with gait impairments resulting from Parkinson's disease, Traumatic Brain Injury, Stroke, Cerebral Palsy, and Spinal Cord Injury. In order to allow patients practice (e.g., voluntary change of walking speed in a natural way), software has been developed that automatically updates the velocity of a treadmill following the intention of the person walking on the treadmill. The invention uses a swing foot velocity measurement to control the velocity of the treadmill which can quickly and precisely detect the user's intention of changing walking velocity. Swing foot velocity measurement allows users to voluntarily change walking velocity while they have a realistic feel of walking (such as over-ground walking). We are seeking a CRADA collaborator to expand implementation of the invention into a fully integrated system that can control treadmill velocity in real time and can be reliably adapted to typical commercial treadmills. CRADA Opportunity: The National Institutes of Health Clinical Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize “A system and method for automatic speed adaptation control of a treadmill for patients.” Please contact Dr. Hyung S. Park at 301-451-7533 for more information.

Selective 12-Human Lipoxygenase Inhibitors for the Treatment of Diabetes and Clotting

Thu, 17 Feb 2011 11:00:00 GMT

This invention discloses small molecule inhibitors of human 12-lipoxygenase (12-hLO). 12-lipoxygenase expression, activation, and lipid metabolites have been implicated in type 1 and type 2 diabetes, cardiovascular disease, hypertension, Alzheimer’s, and Parkinson’s disease. The development of 12-hLO inhibitors may be a potent intracellular approach to decreasing the ability of platelets to form large clots in response to vessel injury or activation of the coagulation pathway. Thus, 12-hLO inhibition has the potential to attenuate platelet-mediated clot formation caused by diabetes and/or cardiovascular disease and significantly decrease the occurrence of myocardial infarction and death. Moreover, Type 1 and Type 2 diabetes are serious disorders that can lead to major complications and reduced lifespan. An unmet medical need is to identify new ways to protect beta cells in these metabolic disorders. A selective 12-hLO inhibitor could provide a new therapeutic approach to prevent or treat either form of diabetes. CRADA Opportunity: The NIH Chemical Genomics Center (NCGC), National Human Genome Research Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these 12-hLO inhibitors. Please contact Dr. David Maloney at maloneyd@mail.nih.gov for more information.

Versatile Melanoma Antigen Family A3 (MAGE-A3) Specific Human T Cell Receptors to Treat Cancer that also Recognize Other MAGE-A Antigen Superfamily Members

Thu, 17 Feb 2011 16:00:00 GMT

Current approaches for treating cancer can also generate harsh side effects in patients and many cancer patients do not respond to generalized chemotherapy and radiation. New and improved therapeutic strategies need to be characterized by reduced side-effects and enhancements in specific anti-tumor activity in individual patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual’s innate and adaptive immune system to fight against specific diseases, such as cancer. Scientists are aiming to improve cell transfer therapies by targeting an increasing collection of tumor antigens with more effective immune cell cultures.

T cell receptors (TCRs) are specialized proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of a variable domain that recognizes the antigen and a constant region that anchors the TCR to the membrane and transmits recognition signals by interacting with other proteins. When a TCR is activated by recognizing its antigen, such as a tumor antigen, signaling pathways are triggered in the cell to produce cytokines that mediate the immune response.

Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to recognize melanoma antigen family A3 (MAGE-A3) peptide antigens. MAGE-A superfamily antigens, including MAGE-A3, are expressed primarily by tumor cells from a variety of cancers. Other than germ cells of the testis, normal cells do not express MAGE-A3 and other MAGE-A proteins, which makes these antigens ideal targets for developing cancer immunotherapies. There are twelve (12) known MAGE-A genes designated A1 – A12. The normal function of MAGE-A3 is not completely known, but in cancerous cells it appears to mediate fibronectin-controlled tumor growth and spreading. MAGE-A3 is one of the most widely expressed cancer testis antigens (CTAs) on human tumors and its expression increases as the cancer progresses to more advanced stages. The T cell receptors (TCRs) developed by these NIH scientists have specificity for MAGE-A3 and MAGE-A12 and deliver a robust immune response when they encounter tumor cells expressing these antigens. These TCRs also recognize MAGE-A2 and/or MAGE-A6, but to a lesser extent that MAGE-A3 and MAGE-A12. The ability to recognize antigens from multiple MAGE-A family members could allow these TCRs to be utilized in the treatment of multiple types of cancer in a wide array of cancer patients. Infusing cancer patients with MAGE-A3 specific T cells via adoptive immunotherapy could prove to be a powerful approach for selectively attacking tumors without generating toxicity against noncancerous cells. CRADA Opportunity: The National Cancer Institute Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of anti-MAGE-A T-cell receptors for the adoptive immunotherapy of cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Terahertz Spatial Light Modulator System for Adaptive Near-Field Imaging

Thu, 17 Feb 2011 21:00:00 GMT

The invention offered for licensing is in the field of imaging microscopes and relates to a terahertz light modulator system, and in particular to a terahertz spatial light modulator system for adaptive near-field imaging.

More specifically, the invention relates to a spatial light modulator system for adaptive near-field imaging having an optical source for transmitting an optical beam through a filter which is controlled to convert the optical light beam into a filtered optical light beam to define one or more transmission pathways through a photoconductive material. The system further includes a terahertz light source for transmitting a terahertz beam through one or more transmission pathways defined by the filtered optical light beam through the photoconductive material for illuminating and scanning the sample without the use of moving structural components. The device would allow micron-scale spatial resolution, would remove the need to mechanically scan a sample, and would allow automatic adjustment of image resolution and transmitted terahertz power. The near-field terahertz microscope of the invention could have a compact, fiber-coupled sensor head with no moving parts — ideal for scientific, medical, and industrial applications like crystal growth optimization, skin cancer diagnosis, and semiconductor chip inspection. In one application, such as "one-cut" surgery, the compact sensor head of the terahertz imaging system has the capability of distinguishing healthy cells from cancerous cells with micron-scale spatial resolution by immediately identifying a skin cancer margin without the need for laboratory work or additional surgery. In another application, the terahertz imaging system may be used in nondestructive semiconductor chip inspection since the terahertz imaging system provides micron-scale spatial resolution. CRADA Opportunity: The National Institute of Biomedical Imaging and Bioengineering is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Hari Shroff at hari.shroff@nih.gov or 301-435-1995 for more information.

Allele Specific shRNA for Nanog, and Its Use to Treat Cancer

Fri, 21 Jan 2011 02:00:00 GMT

Cancer stem cells are currently thought to be major participants in resistance to radiation therapy and chemotherapy; they are also thought to drive the spread of cancer through metastasis. It has been postulated that genes involved in early embryogenesis, primarily transcription factor Nanog but also Oct4 and SOX2, may be reactivated to maintain the properties of cancer stem cells, any treatment that inhibits such genes may therefore inhibit the progression of cancer and lead to improved survival and other clinical outcomes.

The NIH investigators discovered that the expression of NanogP8, a pseudogene of Nanog, is upregulated in human colorectal cancer spheroids formed in serum-free medium. NanogP8 has also been reported to be upregulated in human prostate cancer and glioblastomas. An inhibitory RNA molecule was identified by the investigators to knock down expression of NanogP8, without interfering with expression of Nanog. The discovery may improve the safety of a shRNA-based gene therapy and improve its chances for acceptance as a clinical therapy. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this specific gene therapy to target colorectal and other human carcinomas. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

HMG3 for Detecting and Treating Diabetes

Thu, 20 Jan 2011 07:00:00 GMT

This invention relates to the use of High Mobility Group N 3 (HMGN3) as a marker for detecting diabetes and as a therapeutic agent for treating diabetes.

Diabetes is disabling largely because commonly available anti-diabetic drugs do not adequately control blood sugar levels to completely prevent the occurrence of high and low blood sugar levels. Inappropriate blood sugar levels can be toxic and can cause long-term complications including renopathy, retinopathy, neuropathy and peripheral vascular disease. Those with diabetes are also at risk for developing related conditions such as obesity, hypertension, heart disease and hyperlipidemia.

This invention relates to the discovery that reduced expression of HMGN3 (also called TRIP7) gives rise to elevated blood glucose levels, reduced serum insulin levels and impaired glucose tolerance. CRADA Opportunity: The National Cancer Institute, Laboratory of Metabolism, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HMGN and related chromatin-binding proteins in the function of pancreatic islet cells. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Fluoroquinolone Derivatives as Inhibitors of Human Tyrosyl-DNA Phosphodiesterase (Tdp1)

Thu, 20 Jan 2011 12:00:00 GMT

Chemotherapy can provide therapeutic benefits in many cancer patients, but it often ultimately fails to cure the disease since cancer cells can become resistant to the chemotherapeutic agent. To overcome these limitations, additional strategies are needed to restore or amplify the effect of antitumor agents. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme involved in the repair of DNA lesions created when the activity of the Topoisomerase 1 (Top1) is inhibited. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin. By reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors.

The NIH investigators discovered fluoroquinolone derivatives as specific Tdp1 inhibitors that could potentiate the pharmacological action of Top1 inhibitors, which are currently used in cancer treatment. The instant invention discloses a method of treating cancers with a therapeutically effective amount of a Top1 inhibitor, and a fluoroquinolone derivative that inhibits Tdp1 activity. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Pharmacology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tyrosyl-DNA-phosphodiesterase inhibitors. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

A Computer Program to Predict Optimal Sites on Protein Sequences for Production of Peptide-Directed Antibodies (NHLBI AbDesigner)

Thu, 20 Jan 2011 17:00:00 GMT

The invention offered for licensing is a computer program called "NHLBI AbDesigner" that allows the user to input a unique identifier for an individual mammalian protein to be analyzed in order to find out what short peptides in its amino sequence would most likely result in a strong immunogenic response when injected into a research animal. The software displays standard predictors of immunogenicity and antigenicity in easy-to-view heat maps and also allows users to choose peptides most likely to elicit antibodies that are specific to said protein. The computer code is written in Java and would be made available in the form of .jar files.

For additional information please refer to: https://dirweb.nhlbi.nih.gov/labs/LKEM_G/LKEM/Pages/Antibodydesignsoftware.aspx. CRADA Opportunity: The NHLBI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Brian Bailey, Ph.D. at 301-594-4094 or bbailey@mail.nih.gov for more information.

Diagnosis and Treatment of Cancer Through NUAK2 Assessment and Modulation

Fri, 07 Jan 2011 22:00:00 GMT

The present invention describes that high levels of expression of both NUAK2 and phosphor-Akt at Ser473 (p-Akt) predict the survival of patients with acral melanomas and that modulation of NUAK2 expression using gene therapy approaches effectively suppresses tumor growth of melanoma cells. Furthermore, a CDK inhibitor targeting CDK2, which is a downstream target of NUAK2, effectively suppresses the tumor growth of melanoma cells with NUAK2 amplification. CRADA Opportunity: The National Cancer Institute, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the regulation of NUAK2 function as a strategy to treat melanoma and predict the survival of patients with acral melanomas. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

GATA-3 Reporter Plasmids for Revealing Underlying Mechanisms in Breast Cancer

Wed, 22 Dec 2010 03:00:00 GMT

Scientists at the National Institutes of Health (NIH) have developed GATA-3 gene reporter plasmids that express a green fluorescent protein (GFP) or luciferase reporter protein under the control of a GATA-3 promoter. Cells expressing this plasmid will glow fluorescent green or emit light energy, respectively, if GATA-3 gene expression is activated in the cells. The reporter construct allows cells where GATA-3 gene expression is activated to be isolated and collected for further analysis or be monitored in the host environment.

GATA-3 is a transcription factor that is highly expressed in several types of cells and is a critical transcription factor for the development of particular lineages of hematopoietic cells and normal mammary luminal epithelium. GATA-3 plays a regulatory role in determining the fate of cells in the hematopoietic systems and the mammary gland. Disruption of GATA-3 expression leads to defects in the development of sub-types of lymphoid cells and luminal mammary epithelial cells. GATA3 expression is highly associated with luminal sub-types of breast cancer, whereas expression of GATA3 is low or undetectable in basal subtypes of breast cancer which often have a poor prognosis. Low or limited GATA-3 expression is correlated with larger tumors, increased likelihood of tumor-positive lymph nodes, and predicts an overall poorer clinical outcome compared to patients with higher mammary GATA-3 expression. Researchers believe that a better understanding of GATA-3 function and its dysregulation during the onset and progression of breast cancer will lead to new strategies in diagnosing and treating the disease. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cancer Biology and Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize GATA-3 Reporter Plasmids for Revealing Underlying Mechanisms in Breast Cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Modulators of Survival Motor Neuron Production

Thu, 09 Dec 2010 08:00:00 GMT

This technology discloses compounds that modulate the amount of Survival Motor Neuron protein (SMN). Low levels of SMN protein are associated with Spinal Muscular Atrophy (SMA), which constitutes a group of inherited diseases that cause progressive muscle degeneration leading to death. Consequently, therapeutic inventions have focused on increasing SMN protein levels. This invention discloses novel arylthiazolyl piperidines which are shown to be modulators of SMN production. This invention also discloses methods of treating SMA by administering SMN protein modulators. CRADA Opportunity: The NIH Chemical Genomics Center (NCGC), National Human Genome Research Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these SMN modulator compounds. Please contact Dr. Juan Marugan at maruganj@mail.nih.gov for more information.

Use of Sterculic Acid to Treat Choroidal Neovascularization

Wed, 08 Dec 2010 13:00:00 GMT

Sterculic acid is a naturally occurring cyclopropene acid present in kapok seed oil, cottonseed oil, and in the seeds of the Sterculia foetida tree. Sterculic acid has been reported to be a non-specific inhibitor of stearoyl-Co desaturase (SCD), which has been implicated in several disease states, including cardiovascular disease, obesity, non-insulin-dependent diabetes mellitus, skin disease, hypertension, neurological diseases, immune disorders and cancer (Ntambi JM, J. Lipid Res., 1999, 40(9):1549-1558). NIH investigators have recently discovered that sterculic acid inhibits the neovascularization of the chick chorioallantonic membrane demonstrating that this compound exhibits a potent anti-angiogenic activity. Further, the NIH investigators have shown that sterculic acid inhibits the formation of choroidal neovascularization in the retina of laser treated rats. These results suggest that sterculic acid possesses anti-angiogenic effect likely through regulating genes involved in the angiogenic process.

The present invention is directed to methods of using sterculic acid for the treatment of inflammation, in particular, 7-ketocholesterol mediated inflammation, 7-ketocholesterol cytotoxicity, or unregulated angiogenesis. Diseases mediated by 7-ketocholesterol-induced inflammation and 7-ketocholesterol cytotoxicity include atherosclerosis age-related macular degeneration, and Alzheimer's disease. Diseases mediated by unregulated angiogenesis include certain cancers and age-related macular degeneration. Also disclosed are methods of treating atherosclerosis or Alzheimer's disease using sterculic acid. CRADA Opportunity: The National Eye Institute (NEI), Laboratory of Retinal Cell and Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize sterculic acid, and its derivatives for the treatment of diseases related to angiogenesis or mediated by 7-ketocholesterol-induced inflammation. Please contact David L. Whitmer, Technology Development Coordinator, NEI, at 301-496-4876 or whitmerd@mail.nih.gov for more information. Click here to view the NEI collaborative opportunity announcement.

Nitisinone for Treatment of Oculocutaneous/Ocular Albinism and for Increasing Pigmentation

Wed, 08 Dec 2010 18:00:00 GMT

Albinism (also called achromia, achromasia, or achromatosis) is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes due to absence or defect in any one of a number of proteins involved in the production of melanin. Certain forms of albinism are known to be due to mutations in tyrosine metabolism. In oculocutaneous albinism (OCA), pigment is lacking in the eyes, skin and hair. In ocular albinism, only the eyes lack pigment. Patients with albinism experience varying degrees of vision loss associated with foveal hypoplasia, nystagmus, photophobia and/or glare sensitivity, refractive errors, and abnormal decussation of ganglion cell axons at the optic chiasm. Current treatment options for vision problems caused by albinism are limited to correction of refractive errors and amblyopia, low vision aids, and (in some cases) extraocular muscle surgery.

Nitisinone (NTBC) is an FDA-approved drug used in the treatment of tyrosinemia, type 1. The drug blocks the normal degradation pathway of tyrosine thus allowing greater circulating plasma levels of tyrosine. NIH investigators have identified that administration of NTBC to subjects (e.g., mice or humans) with certain forms of albinism, can result in increased circulating tyrosine levels, an increase in tyrosinase activity, and, subsequently, increased pigmentation.

This technology provides methods for increasing tyrosine plasma concentrations in patients suffering from oculocutaneous albinism or ocular albinism by administering a pharmaceutically acceptable composition of NTBC. Specifically, this technology can be useful in treating patients with type OCA1a albinism, who possess no measurable tyrosinase activity, or type OCA1b albinism, who exhibit greatly diminished tyrosinase activity.

Applications for this technology include treatment of impaired vision in patients suffering from oculocutaneous albinism, or ocular albinism, and as a treatment for increasing pigmentation in the eyes, hair and/or skin of patients. CRADA Opportunity: The National Eye Institute, Ophthalmic Genetics and Visual Function Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of nitisinone (NTBC) for oculocutaneous albinism or as a treatment for increasing pigmentation in the eyes, hair and/or skin of patients. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information. Click here to view the NEI collaborative opportunity announcement.

Pyruvate Kinase M2 Activators for the Treatment of Cancer

Wed, 08 Dec 2010 23:00:00 GMT

NIH investigators have discovered a series of small compounds with the potential to treat a variety of cancers as well as hemolytic anemia. Contrary to most cancer medications, these molecules can be non-toxic to normal cells because they target a protein specific to the metabolic pathways in tumors, thus representing a significant clinical advantage over less-specific chemotherapeutics.

The invention described here is a series of small molecules that activate pyruvate kinase (PK) isoform M2. PK-M2 is a critical metabolic enzyme that is affected in all forms of cancer. Inactivation of PK-M2 leads to a buildup of metabolic intermediates inside the cell. Tumor cells require a buildup of metabolic intermediates in order to undergo rapid cell growth and proliferation. Hence, activation of PK-M2 in tumor cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation or destroy the tumor cells. Further, while in normal post-embryonic cells only PK isoforms R, L, or M1 are active, in all tumors only PK-M2 is active. So, PK-M2 activation would affect only tumor cells, and small-molecule PK-M2 activators may not be toxic to healthy cells.

This invention discloses the use of two new small molecule pharmacophores that can activate PKM2 through the allosteric site: 3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-sulfonamides, and 2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamides. CRADA Opportunity: The NIH Chemical Genomics Center (NCGC), National Human Genome Research Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these pyruvate kinase M2 activators. Please contact Dr. Matthew Boxer at boxerm@mail.nih.gov for more information.

Synovial Sarcoma X Breakpoint-2 (SSX-2) Specific Human T Cell Receptors for Treating a Wide-Range of Cancers

Sat, 27 Nov 2010 04:00:00 GMT

Many current approaches for treating cancer also generate harsh side effects in patients. In addition, a sizable patient population does not respond to generalized chemotherapy and radiation treatments for cancer. There is an urgent need to develop new therapeutic strategies aimed at reducing side-effects and increasing specific anti-tumor activity in individual patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual’s innate and adaptive immune system to fight against specific diseases, including cancer. As research and development continues in this area, scientists continue to improve cell transfer therapies by targeting an increasing collection of tumor antigens with more effective immune cell cultures.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response.

Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to recognize synovial sarcoma X breakpoint-2 (SSX-2) peptide antigens. SSX proteins, including SSX-2, are expressed primarily by tumor cells from a variety of cancers, including pancreatic cancer where very few treatment options exist. Other than germ cells of the testis, normal cells do not express SSX proteins and, thus, should not be targeted by therapies directed against these proteins. Therefore, SSX proteins represent a promising target for cancer immunotherapy. There are ten (10) known members of the SSX protein family designated SSX-1 through SSX-10. The T cell receptors (TCRs) developed by these NIH scientists have specificity for SSX-2 and deliver a robust immune response when they encounter SSX-2 expressing cells. However, these TCRs also recognize five (5) other SSX family members, including SSX-3, SSX-4, SSX-5, SSX-9, and/or SSX-10, and deliver a productive, intermediate immune response in the context of target cells expressing these antigens. This versatile antigen coverage could allow these SSX-specific TCRs to be utilized in the treatment of multiple types of cancer in a wide array of cancer patients. Infusing cancer patients with SSX-2 specific T cells via adoptive immunotherapy could prove to be a powerful approach for selectively attacking tumors without generating toxicity against noncancerous cells. CRADA Opportunity: The National Cancer Institute, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of T cell receptor gene therapy for the treatment of cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Novel Compositions and Methods to Treat Glioblastoma and Other Cancers

Fri, 26 Nov 2010 09:00:00 GMT

There remains a significant unmet need for therapeutics to treating glioblastoma multiforme, a very aggressive type of brain tumor. Glioblastoma is difficult to treat with conventional surgery, chemical, and radiation therapies. With approximately 18,000 new glioblastoma cases in the U.S. each year, and a comparable market in Europe, the global market for such products forecast to be over $300 million. In light of the high unmet need in malignant astrocytoma and little in the way of pipeline competition, this indication represents a potential easy route to market for new drugs.

Researchers at the National Cancer Institute (NCI) have identified two novel molecular targets, annexin 1 (Anx A1) and its receptor formyl peptide receptor 1 (FPR1), for new anti-glioblastoma therapies. Anx A1 and FPR1 mediate growth, invasion, production of angiogenic factors, tumor formation, and are abnormally expressed by more highly malignant glioblastomas. Depletion of Anx A1 in glioblastoma cells resulted in their reduced capacity to form tumors; additional depletion of FPR1 further reduced this capacity. Further, the NCI researchers have found a correlation between Anx A1 expression and the degree of malignancy of human gliomas.

Novel anti-glioblastoma therapies encompassed by this invention include neutralizing antibodies against Anx A1 and FPR1, small compound agonists of Anx A1 and FPR1, small interference RNAs (siRNAs) that deplete Anx A1 and FPR1 from glioblastoma cells, as well as delivery methods to effectively administer the Anx A1 and FPR1 targeting drugs into brain tissues. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Immunoregulation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Targeted Anti-Cancer Compounds for Treating Chromosomal Instability Syndromes

Fri, 26 Nov 2010 14:00:00 GMT

At $47 billion, cancer is one of the largest, fastest growing markets in the pharmaceutical industry. There remains a significant unmet need for new therapeutics that target cancer cells while sparing normal cells. Cancer cells show higher levels of DNA damage than normal cells, and therefore rely more heavily than normal cells on DNA repair mechanisms for survival. There is a particular need for cancer therapies for cancer-prone chromosomal instability syndromes such as Ataxia Telangiectasia, Nijmegen Breakage, Bloom, and Fanconi’s anemia, which result from dysfunctional DNA repair systems.

Researchers at Columbia University and the National Cancer Institute (NCI) have developed compositions and methods of useful in the treatment of cancer and in the sensitization of cancer cells to cancer therapy. The compositions target the MRE11-RAD50-NBS1 (MRN) complex, a DNA repair complex essential for sensing and responding to DNA damage.

Given the dependency of cancer cells on DNA repair systems, they are susceptible to compositions that inhibit DNA damage repair. Thus, cancers that already have one or more defects in DNA repair systems, such as those from patients with chromosomal instability syndromes, are effectively treated with the present compositions. CRADA Opportunity: The National Cancer Institute, Division of Cancer Prevention, Chemopreventive Agent Development Research Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents for the prevention and treatment of cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

ERBB4 Mutations Identified in Human Melanoma Metastasis Cell Lines (2690, 2379, 2197, 2183, 2535, 2645, 1770, 2359, 2238, 2319, 2190)

Fri, 26 Nov 2010 19:00:00 GMT

Protein tyrosine kinases (PTKs) have been associated with a wide variety of cancers, including melanoma. Using high-throughput gene sequencing, the NIH has analyzed PTKs in melanoma and identified several novel somatic alterations, including alterations in ERBB4 (also called HER4). These mutations were found to increase the sensitivity of cells in which they reside to small molecule inhibitors, such as lapatinib.

Available for licensing are several melanoma cell lines that harbor ERBB4 mutations. These cell lines provide methods of identifying specific inhibitors to ERBB4 that could be used to treat patients with ERBB4 mutations as well as methods to further understand the role of ERBB4 mutations in melanoma. Given the recent success of small molecule protein kinase inhibitors and specifically inhibitors to epidermal growth factor receptor (EGFR) (such as gefinitib and erlotinib), these reagents could be used to further the development of specific inhibitors to ERBB4 and improve existing melanoma treatments for patients with these mutations. CRADA Opportunity: The National Human Genome Research Institute’s Cancer Genetics Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate and/or commercialize these newly characterized ERBB4 mutant cell lines as well as to identify and test ERBB4 inhibitors as possible therapeutic drug candidates to treat melanoma and other cancers. Please contact Dr. Yardena Samuels at samuelsy@mail.nih.gov for more information.

Isocitrate Dehydrogenase 1 (IDH1) R132 Mutation Human Melanoma Metastasis Cell Line

Sat, 27 Nov 2010 00:00:00 GMT

Isocitrate dehydrogenase 1 (IDH1) plays an important role in glucose metabolism in the cytoplasm, converting isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+ to NADPH). However, when IDH1 harbors a R132 mutation it results in the accumulation of 2-hydroxyglutarate and has a corresponding association with cancer. This mutation in IDH1 has previously been identified in approximately 80% of progressive gliomas and 10% acute myeloid leukemias (AML). In contrast, this mutation is very rare in other cancers. Therefore, additional research on the IDH1 R132 mutation could be useful for diagnostic, prognostic, and therapeutic purposes.

The researchers at the NIH have developed a human melanoma cell line designated 2633, which harbors the IDH1 R132C mutation. The inventors used low passage cell lines derived from a panel of confirmed metastatic melanoma tumor resections, paired with apheresis-collected peripheral blood mononuclear cells to identify IDH1 mutations. Sequencing of IDH1 in this panel allowed them to discover a melanoma cell line with the IDH1 R132C mutation. Until now no such cell line has been found and this has hindered the understanding of the effects mutated IDH1 has on cancer progression as well as the development of drugs that would be specific for cells that harbor this mutation. Use of this cell line will allow researchers decipher the biology of this gene as well as aid in the development of specific inhibitors of its mutated form. CRADA Opportunity: The National Human Genome Research Institute’s Cancer Genetics Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate and/or commercialize this newly identified melanoma-associated gene as a diagnostic marker as well as utilize the IDH1 R132 cell line to identify and test IDH1 inhibitors as possible therapeutic drug candidates to treat melanoma and other cancers. Please contact Dr. Yardena Samuels at samuelsy@mail.nih.gov for more information.

Novel Compounds that Specifically Kill Multi-Drug Resistant Cancer Cells

Fri, 26 Nov 2010 05:00:00 GMT

One of the major hindrances to successful cancer chemotherapy is the development of multi-drug resistance (MDR) in cancer cells. MDR is frequently caused by the increased expression or activity of ABC transporter proteins in response to the toxic agents used in chemotherapy. The increased expression or activity of the ABC transporter proteins causes the toxic agents to be removed from cells before they can act to kill the cell. As a result, research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters, thus causing the chemotherapeutic agents to remain in the cell long enough to exert their effects. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects due to the inhibition of ABC transporter function in normal cells, thereby restricting their usefulness as therapeutics.

Investigators at the NIH previously identified novel compounds with the ability to kill multi-drug resistant cancer cells while leaving normal cells relatively unharmed. These “MDR-selective compounds” were not inhibitors of ABC transporters because they killed multi0drug resistant cells without affecting the activity of ABC transporters. Furthermore, their activity was dependent directly on the level of expression of ABC transporters, thus increasing their selectivity for diseased cells. As a result, the undesirable side-effects that have prevented the use of inhibitors of ABC transporters as therapeutics should not affect the therapeutic application of the MDR-selective compounds.

The inventors have now generated third generation MDR-selective compounds with further improved solubility, selectivity and killing activity toward MDR cells. The new MDR-selective compounds selectively kill MDR cancer cells, and their efficacy correlates directly with the level of ABC transporter expression. This suggests that the third generation MDR-selective compounds represent a powerful strategy for treating MDR cancers. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.Click here to view the NCI collaborative opportunity announcement.

Scanningless Multi-photon Microscopy with Diffraction-Limited Axial Resolution

Tue, 09 Nov 2010 10:00:00 GMT

The technology offered for licensing is a scanningless multiphoton microscope for performing 3-dimensional imaging that achieves diffraction-limited resolution. The microscope combines temporal multiplexing with spatial dispersion to achieve diffraction-limited resolution without having to mechanically scan the sample (a field of view up to 30x30 microns). The wide-field excitation of the sample allows imaging rates in excess to prior art multiphoton microscopes while still achieving diffraction-limited axial resolution. The microscope includes a laser source that generates a femtosecond laser beam that passes through a stair-step optic having a variable thickness piece of glass arranged such that each "strip" of the laser beam is delivered at a different relative delay. Each strip exits the stair-step optic and is imaged onto the surface of a diffraction grating by two imaging lenses and a mirror. The diffraction grating sends the different wavelengths that compose each horizontal strip of the laser beam in different directions. Another pair of lenses, such as the imaging lens and objective lens (e.g., high numerical aperture objective) images and de-magnifies the surface of the diffractive grating into a biological sample that causes an excitation to occur in the sample. The ensuing excitation generates fluorescence in the sample confined to the focal plane of the objective lens, where the excitation is maximized. The fluorescence is collected through the objective lens and then by a CCD camera. CRADA Opportunity: The National Institute of Biomedical Imaging and Bioengineering Section on High Resolution Optical Imaging is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this invention. Please contact Dr. Henry Eden at edenh@mail.nih.gov for more information.

Novel Anti-HIV Acylthiol Drugs and Thioether Prodrugs

Tue, 09 Nov 2010 15:00:00 GMT

The inventions provide the compositions, pharmaceutical carrier, and usages of the new Acylthiols (E-329-2000 family) and Thioether pro-drug (E-177-2010 family) compounds in treatment of retroviral infections such as HIV. More specifically, these compounds target the highly-conserved nucleocapsid protein of HIV-1. Activity of these compounds against the nucleocapsid protein leads to inactivation of the virus via disruption of the zinc fingers, integral for infectivity, without significantly affecting cellular proteins. Finally, these inventions can be prepared from inexpensive starting materials and two “one-pot” reactions. Thus, they open the possibility for an effective drug treatment for HIV that could reach underdeveloped countries. These new compounds have the potential to be used both as a systemic drug for the treatment of HIV-1 infection and as a topically-applied barrier to prevent viral transmission. CRADA Opportunity: The Laboratory of Cell Biology, Center for Cancer Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the above invention for the treatment/prevention of HIV infection. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

System for Magnetic Resonance Spectroscopy of Brain Tissue for Pattern-based Diagnostics

Fri, 29 Oct 2010 19:00:00 GMT

Available for licensing and commercial development is a system for preprocessing magnetic resonance spectroscopy (MRS) data of brain tissue for pattern-based diagnostics. The MRS preprocessing system includes an MRS preprocessing module that executes an operation that normalizes MRS spectrum data, recalibrates and scales the normalized MRS spectrum data, and then renormalizes the scaled MRS spectrum data. The resulting preprocessed MRS data is used to assist in identifying abnormalities in tissues shown in MRS scans. Raw MRS spectrum data and scaling the raw MRS spectrum data is achieved by a plurality of weighting constants to generate a preprocessed MRS spectrum data. The method may also include providing raw MRS spectrum data, recalibrating the raw MRS spectrum data, and scaling the recalibrated MRS spectrum data by using a plurality of weighting constants to generate a preprocessed MRS spectrum data. CRADA Opportunity: The FDA National Center for Toxicological Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize FDA’s magnetic resonance spectroscopy technology in various imaging and diagnostic applications. Please contact Alice Y. Welch, Ph.D. at 301-796-8449 or alice.welch@fda.hhs.gov for more information.

Stimulation of Natural Killer T-cell Anti-tumor Activity

Wed, 27 Oct 2010 23:00:00 GMT

Natural killer T cells (NKT) are a unique lymphocyte population that has T-cell and NK cell functional properties in order to rapidly elicit an immune response. alpha-galactosylceramide (alpha-GalCer) is a potent NKT stimulator and induces of IFN-gamma release to promote immunity against tumors and infectious agents. Humans have natural antibodies against alpha-galactose, which may be one of the reasons why the human clinical trials of alpha-GalCer or KRN7000 were not very successful.

Investigators at the National Cancer Institute have found that beta-mannosylceramide (beta-ManCer) promotes immunity in an IFN-gamma independent mechanism. beta-ManCer is a new class of NKT agonist that induces immune responses alone, through nitric oxide and TNF-alpha-dependent mechanisms, or synergistically with alpha-GalCer to enhance alpha-GalCer’s efficacy. Since beta-ManCer does not have alpha-galactose, which can be neutralized by natural antibodies, patients could be treated with multiple doses without negative side effects associated with the loss of IFN-gamma production. Hence, beta-ManCer is a promising anti-cancer treatment either alone or in combinatorial therapies with alpha-GalCer to selectively induce immune responses. CRADA Opportunity: The Vaccine Branch of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize beta-ManCer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Diagnostic and Prognostic HCC-related Metabolites

Thu, 28 Oct 2010 03:00:00 GMT

Metabolite profiling identifies and measures changes in cellular metabolites as a means to determine a direct correlation between gene expression and changes in biological function. Investigators at the National Cancer Institute have identified a unique set of metabolite biomarkers associated with hepatocellular carcinoma (HCC), early stage HCC, HCC patient outcome and HCC stem-cell subtype. Subsets of this metabolite/gene signature can distinguish HCC tumors from normal tissues with 88-97% accuracy, identify early stage HCC patients with 62-78% accuracy, wherein early stage is defined as TNM stage I, prognose negative patient outcome, and identify a HCC stem cell subtype with 70-77% accuracy. These metabolites and gene surrogates are elements of the PI3K and Myc signaling networks which can potentially be targeted for therapeutic purposes.

HCC represents an extremely poor prognostic cancer, and patients are often diagnosed with end-stage cancer and have poor survival. HCC is also a very heterogeneous disease and often arises from chronic liver disease. Surgery and transplantation remain the only curative option for patients; however, complications due to cirrhosis mean it is a viable option for 5-10% patients. This HCC gene signature can be developed into assays to enable clinicians to accurately diagnose HCC, including early stages and subtype of this disease, and therefore stratify patients for appropriate treatment and prioritizing liver transplantation candidates based on their metabolite profile. CRADA Opportunity: The Center for Cancer Research, Laboratory of Human Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize metabolomic signatures for liver cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Modified POTE Peptides for Cancer Immunotherapy

Thu, 21 Oct 2010 07:00:00 GMT

Investigators at the National Cancer Institute have identified and enhanced immunogenicity of POTE epitopes to improve their efficacy in cancer vaccines. POTE is a novel tumor antigen expressed in a variety of cancers including breast, prostate, colon, lung, ovary, and pancreas cancers. POTE has limited expression in normal tissues and therefore a specific target for cancer treatments, including immunotherapy. Immunotherapy has great potential as a cancer therapeutic because of its specificity and freedom from toxic effects of chemotherapies.

Antigen-specific cancer immunotherapy often relies on identification of epitopes expressed by cancer cells that can be targeted by cytotoxic T cells (CTL). However, the CTL repertoire against high-affinity cancer epitopes is often ineffective because cancer epitopes may share a similar structure to natural “self” antigens. As a result, cancer cells are not recognized by CTLs and destroyed. The enhanced POTE epitopes induce a stronger immune response than natural responses. These modified epitopes are more effective at inducing CTL against POTE expressing cancer cells and have greater potential to serve as cancer vaccine targets. CRADA Opportunity: The Center for Cancer Research, Vaccine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

IL-10 and IFN-gamma Peptide Inhibitors

Thu, 21 Oct 2010 11:00:00 GMT

Available for licensing are several potent and selective inhibitors of IL-10 and IFN-gamma signaling. Although cytokines play important roles in cancer and inflammation, there are no specific inhibitors of any cytokines to date. IL-10 and IFN-gamma cytokine signaling play crucial roles in inflammation, cancer growth, and autoimmune diseases. The investigators have developed short peptides that potently and selectively interfere with dimerization of the cytokines and their binding to the corresponding receptor. Included in the patent application are also metabolically stable lipopeptides mimicking conserved regions of IL-10 and IFN-gamma receptors that interfere with STAT3 and STAT1 phosphorylation and subsequent signaling. Lipopeptides potently inhibit STAT3 and STAT1-dependent growth of cancer cells. These compounds are promising drug candidates for the treatment of cancer and many infectious and inflammatory diseases. CRADA Opportunity: The Center for Cancer Research, Cancer and Inflammation Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of IL-10, IFN-gamma and STAT3 signaling. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Immunotoxin for the Treatment of Neuroblastoma Relapse

Thu, 21 Oct 2010 15:00:00 GMT

Immunotoxins are proteins which have two distinct domains: (1) an antibody or antibody binding fragment which is capable of recognizing a single specific cell surface protein and (2) a toxin domain which is capable of inducing cell death. Immunotoxins are currently being pursued as therapeutics because they specifically kill diseased cells while leaving essential, healthy cells alone. This increases the effectiveness of the therapy while reducing the appearance of side-effects. A particular immunotoxin that is being studied in clinical trials consists of an anti-CD22 antibody binding fragment and a mutated Pseudomonas exotoxin A. Although this immunotoxin is being explored primarily as a treatment for hematological malignancies, it can be used to treat any condition where CD22 is overexpressed on the cell membrane of diseased cells.

Neuroblastomas are malignant cancers that start in nerve tissue and primarily affect infants and children. Although frontline treatments for neuroblastoma are often effective, relapse frequently occurs in high risk cases. The most common form of relapse in neuroblastoma patients is caused by Neuroblastoma tumor initiating cells (NB-TIC). Therefore, if NB-TIC could be eliminated, high risk neuroblastoma patients could have a therapeutic option for preventing a relapse.

This invention concerns the discovery that NB-TIC expresses CD22. As a result, NB-TIC are susceptible to treatment with an anti-CD22 immunotoxin. By combining frontline neuroblastoma treatments with anti-CD22 immunotoxins, both the primary neuroblastoma and cells capable of initiating a relapse can be eliminated. As a result, even high risk neuroblastoma patients should have an increased chance of surviving neuroblastoma. CRADA Opportunity: The Center for Cancer Research, Pediatric Oncology Branch and Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize recombinant anti-CD22 immunotoxins for the treatment of neuroblastoma. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Novel Prognostic and Therapeutic Biomarker for Cancer and Inflammatory Diseases

Thu, 21 Oct 2010 19:00:00 GMT

There remains a significant unmet need for diagnostics, prognostics, and therapeutics for conditions that involve inflammation and the formation of blood clots such as bleeding disorders, trauma, and diseases such as sepsis, cardiovascular disease, stroke, and cancer. The global market for such products is varied and competitive, and is forecast to be over $40 billion by 2010.

Researchers at the National Cancer Institute (NCI) have identified that levels of a novel soluble protein involved in the repair mechanism for damaged blood vessels correlate with outcome in sepsis and with the diagnosis of disseminated intravascular coagulation, a contributing factor to the morbidity and mortality associated with sepsis.

Further, the NCI researchers have demonstrated that a recombinant version of this novel protein facilitates the clotting of blood, suggesting a potentially significant therapeutic benefit for the treatment of bleeding disorders or trauma. CRADA Opportunity: The Center for Cancer Research, Cancer and Inflammation Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize soluble TREM receptor proteins. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Soluble Glypican-3 Protein for Treatment of Cancer

Thu, 21 Oct 2010 23:00:00 GMT

Hepatocellular carcinoma (HCC) is a form of liver cancer that is among the more deadly cancers in the world. HCC is typically only detected at the later stages of cancer development, which is always associated with poor prognosis. Because HCC is often associated with liver disease, traditional chemotherapy is not an option, making surgery the most common form of treatment. As a result, there is a need for new treatments.

Glypican-3 (GPC3) is a cell surface protein that is normally involved in cell growth and differentiation. GPC3 has been shown to act through the Wnt-signaling pathway, a pathway that is often activated in a number of different cancer cell types. Significantly, the ability of GPC3 to activate signaling through Wnt requires that GPC3 be bound to the cell membrane. GPC3 is also preferentially expressed on HCC cells, suggesting it could play a particularly important role in tumorigenesis in HCC.

This invention concerns a soluble form of GPC3 that lacks its cell membrane anchoring domain. This soluble form of GPC3 maintains its ability to interact with the Wnt signaling pathway, but cannot induce the activation of the pathway because it is not bound to the cell membrane. By competing with fully functional GPC3, the soluble GPC3 is able to inhibit the growth of HCC cells, thereby decreasing the ability of tumors to grow and metastasize. This suggests that soluble GPC3 represents a possible therapeutic for HCC. CRADA Opportunity: The National Cancer Institute, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Prevention and Treatment of Herpes Virus Infection by Inhibition of the JMJD2 Family of Histone Demethylases

Wed, 13 Oct 2010 03:00:00 GMT

Investigators at the NIH have discovered a potential means for preventing or treating a herpes virus infection by inhibiting the activity of the host cell’s histone demethylases. When herpesviruses enter a cell, they are inactivated by cellular defense mechanisms that wrap the viral genome in repressive chromatin structures. In order for viral replication to progress, the host’s own histone demethylases are recruited to the viral genome to reverse this repression. In a preceding invention, the laboratory disclosed that viral replication and reactivation can be significantly reduced through inhibition of the histone demethylase LSD1 using Mono-Amino Oxidase Inhibitors (MAOIs); drugs that are in clinical use. The current invention further discloses that inhibition of a second set of histone demethylases (JMJD2 family) using a specific JMJD2 inhibitor, dimethyloxaloylglycine (DMOG), also results in significant repression of herpes viral replication.

Either alone or in combination, small molecule inhibition of LSD1 and the JMJD2 family present novel approaches for preventing herpes virus infection and halting viral reactivation that can lead to a disease that ranges from mild core sores to herpesvirus keratitis and life threatening encephalitis. Additionally, chromatin-mediated repression of viral genomes and the requirement to de-repress these genomes for productive infection appears to be general to herpesviruses. Therefore, this treatment could also be applicable to chicken pox, shingles, CMV disease, mononucleosis, and Kaposi's sarcoma. CRADA Opportunity: The NIAID Laboratory of Viral Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize prevention and treatment of viral diseases. Please contact Thomas Kristie, Ph.D. at 301.496.3854 or tkristie@niaid.nih.gov for more information.

Inverse Agonists of the TSH Receptor for the Treatment of Thyroid Cancer and Hyperthyroidism

Tue, 12 Oct 2010 07:00:00 GMT

This technology features small molecule inverse agonists of the thyroid-stimulating hormone (TSH) receptor that may be readily synthesized, and are likely to prove effective for oral administration. These compounds may potentially be used to treat recurrent thyroid cancer and some cases of hyperthyroidism, and also represent unique tools for investigating the role of TSH receptor signaling in these diseases.

According to the National Cancer Institute, over 37,000 new cases of thyroid cancer were diagnosed in the United States in 2008. Approximately 10% to 30% of patients thought to be disease-free after initial treatment will develop recurrent cancer or metastases, and unless the recurrence is detected early, the prognosis is generally poor.

As the TSH receptor is known to stimulate proliferation of thyroid cancer cells, it has been suggested that suppression of basal TSH receptor signaling may improve outcomes in the treatment of recurrent thyroid cancer. The compounds disclosed in this technology suppress basal signaling by the TSH receptor, and are thus excellent candidates for a suppression-based treatment approach. CRADA Opportunity: The NIDDK Office of Technology Transfer and Development is seeking statements of capability or interest from parties interested in collaborative research to further develop inverse agonists of the TAS receptor. Please contact Marguerite J. Miller at 301-496-9003 or millermarg@mail.nih.gov for more information.

Compositions and Methods for the Treatment of Cancer

Mon, 27 Sep 2010 11:00:00 GMT

Cancer is the second leading cause of human death next to coronary disease in the United States. Worldwide, millions of people die from cancer every year. In the United States alone, as reported by the American Cancer Society, cancer causes the death of well over a half-million people annually, with over 1.2 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise. Cancer is soon predicted to become the leading cause of death in the United States.

This application claims methods for inducing an immune response to a tumor. These methods include administering a therapeutically effective amount of apoptotic tumor cells conjugated to a K-type CpG oligodeoxynucleotide (ODN) to a subject. Methods for treating a tumor in a subject are also claimed in this application. These methods include administering a therapeutically effective amount of apoptotic tumor cells conjugated to a K-type CpG oligodeoxynucleotide (ODN) to a subject. More specifically, the tumor cells may be autologous, and the tumor may be a lymphoma, cervical cancer, prostate cancer, breast cancer, colon cancer, or a lung cancer. CRADA Opportunity: The Center for Cancer Research, Laboratory of Experimental Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Linked Purine Pterin HPPK Inhibitors Useful as Antibacterial Agents

Mon, 27 Sep 2010 15:00:00 GMT

The invention offered for licensing describes and claims novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway which is essential for microorganisms but absent in mammals. These novel inhibitors are based on linked purine pterin compounds. They can disrupt the folate biosynthesis of bacteria and thus can find utility as potential antimicrobials. Antibiotics based on these lead molecules can be specifically designed and synthesized to serve as broad-spectrum or narrow-spectrum antibiotics. None of the currently established antibiotics target HPPK. CRADA Opportunity: The National Cancer Institute, Biomolecular Structure Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the inhibitors of HPPK as novel antibiotics. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

A Rapid, Peripheral Blood Gene Expression Biomarker Panel for Diagnosis of Acute Ischemic Stroke

Mon, 20 Sep 2010 19:00:00 GMT

There are presently no rapid, accurate diagnostic procedures or methods that can be used to determine whether a patient has suffered an acute ischemic stroke (AIS). Current technologies for diagnosis of AIS are limited by speed and resources as well as inaccuracy and generally require a high level of training to interpret the results for medical technicians. In contrast, this invention may lead to the development of a rapid and accurate clinical diagnostic kit that would require very little training for proper use and could be used in the field or the emergency room setting.

Scientists at the National Institutes of Health have discovered that expression levels of a set of nine genes may be used as biomarkers for diagnosis of AIS as well as outcome prediction. These biomarkers may be rapidly identified using peripheral whole blood and may form the basis of a rapid and accurate clinical point of care diagnostic kit.

Further, if validation is positive, this technology may enable rapid differential diagnosis between acute ischemic stroke and hemorrhagic stroke, transient ischemic attack, or any pathology mimicking a stroke. Not only can this be used to identify stroke earlier in the course of treatment, this panel may also help to better characterize stroke subtype, and identify new pathways for stroke treatment. This is important as the only FDA approved treatment for acute ischemic stroke is tissue plasminogen activator (tPA) and tPA must not be given to hemorrhagic stroke patients since it could increase intracranial bleeding. To effectively treat AIS, tPA must be administered intravenously within 3-4 hours of known stroke onset. Because the differential diagnosis of AIS versus hemorrhagic stroke is difficult without specialized imaging equipment such as a CT scan with contrast or an MRI image, only a small percentage of stroke patients (3-5%) are ever given tPA. So, a rapid and accurate clinical diagnostic kit based on this invention would have a profound public health benefit and likely a large commercial potential. CRADA Opportunity: The NINR is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a point of care test for ischemic stroke diagnostics and outcome prediction. Please contact Dr. Taura Barr at 304-293-0503 or barrt@mail.nih.gov for more information.

Small Molecule Neuropeptide S Receptor (NPSR) Antagonists for the Treatment of Addictive Disorders, Mood, Anxiety and Sleep Disorders

Mon, 20 Sep 2010 23:00:00 GMT

The inventors, who work for the National Human Genome Research Institute (NHGRI) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) at the National Institutes of Health (NIH), have developed NPSR antagonists that hold the potential for being clinically useful treatments for alcohol and drug addiction. Neuropsychiatric disorders including, for example, mood, anxiety, eating, and sleep related disorders, as well as alcoholism and drug addiction, are major causes of mortality and morbidity. Patient relapse into drug seeking and use, after an interval of sobriety, is a key component of the addictive syndrome, with approximately two-thirds of patients relapsing within three months of initiating abstinence. Therefore, relapse prevention is a major treatment objective.

Neuropeptide S (NPS), an endogenous ligand for the Neuropeptide S receptor (NPSR) has recently been shown to play a key role in relapse-like behavior. In addition, because mood, anxiety, eating, and sleep related behaviors are often closely linked with the addictive process, and are also affected by the NPS system, it is believed that the NPSR antagonist will also be promising as a useful therapeutic target in these clinical areas as well. CRADA Opportunity: The NIH Chemical Genomics Center (NCGC), NHGRI, NIH is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these NPSR antagonist small molecule compounds for various therapeutic uses including treatment of neuropsychiatric disorders and alcohol and drug addiction. Please contact Dr. Juan J. Marugan at maruganj@mail.nih.gov for more information.

Use of Adenosine Agonists to Prevent Arterial Vascular Calcification Disorder

Tue, 21 Sep 2010 03:00:00 GMT

Scientists at the National Human Genome Research Institute (NHGRI) and the National Heart Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH) have discovered a genetic defect in the Ecto-5’-nucleotidase (NT5E) gene which results in Cluster of Differentiation 73 (CD73) deficiency that leads to a decrease in adenosine, and ultimately, an increase in vascular calcification. NT5E encodes CD73, an enzyme that converts adenosine monophosphate (AMP) to adenosine in the extracellular region of the vascular endothelium. Normally, extracellular adenosine binds to one of the several receptors on the surface decreasing the production of cyclic AMP (cAMP) resulting in an inhibition of vascular calcification.

The discovery of this genetic mutation leading to a decrease in adenosine provides a method of treating or preventing the disorder by using adenosine receptor agonists as therapeutic agents. Adenosine receptor agonists can be used to treat or prevent disorders associated with vascular and/or joint capsule calcification, including for example atherosclerosis, Monkeberg’s medial sclerosis, CD74 deficiency, Ehlers Danlos syndrome (EDS), Marfan/Loewe Dietz syndrome, fibromuscular dysplasia, Kawasaki syndrome, pseudoxanthoma elasticum, and premature placental calcification. CRADA Opportunity: The NHGRI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adenosine receptor agonist compounds for therapeutic use including as a treatment of certain common as well as rare vascular calcification-related disorders (see above Description of Invention). Please contact NHGRI Technology Development Coordinator Claire T. Driscoll at cdriscol@mail.nih.gov for more information.

Transplant and Autoimmune Therapy Using T-Cells Expressing Programmed Death Ligand-1 (PD-L1)

Mon, 20 Sep 2010 07:00:00 GMT

Transplant complications (graft rejection and graft-versus-host disease) and autoimmune diseases are primarily caused by T cell immune responses against normal host tissue or transplanted tissues. These disorders can lead to serious complications and may be chronic, debilitating, and fatal. Current treatment for these disorders is oftentimes not effective, and is typically associated with significant side effects, including global immune suppression, which increases the rate of infection and cancer. Hence, there is a need for new technologies to more specifically suppress the immune system for treatment of these diseases.

Programmed death (PD) ligand 1 (PD-L1) is an immune molecule present on regulatory T cells (Tregs), other suppressor cell populations, and tumor cells; the function of PD-L1 is to suppress the function of pathogenic T cells that express the PD1 receptor. Therefore, it has been hypothesized that the transfer of T cells that are enriched for PD-L1 expression might represent an effective method to suppress autoimmunity or transplant complications. Adoptive T cell therapy using Tregs is one such approach; however, this approach is limited due to the relative rarity of Tregs and their tendency to possess differentiation plasticity towards pathogenic T cell subsets such as the Th17 subset. Ex vivo co-stimulated and expanded effector T cells can be generated in sufficient numbers for cell therapy; however, such cells are not enriched for PD-L1 expression.

The current technology overcomes these limitations through transduction of co-stimulated T cells with a lentiviral expression vector that dictates T cell expression of PD-L1. In this method, the co-stimulated T cells acquire the immunosuppressant characteristics of Treg cells. The PD-L1 gene expression construct co-expresses a cell surface molecule (i.e., CD19 or CD34) that allows enrichment of the gene-modified T cells to high purity. Also the construct co-expresses another gene, TMPK, which acts as a safety cell fate switch because the TMPK can specifically activate the cytotoxic prodrug, AZT. By incorporation of this TMPK/AZT cell fate safety switch, the current technology will allow for PD-L1 therapeutic delivery, with subsequent elimination of the therapeutic cells in the event of toxicity. CRADA Opportunity: The Center for Cancer Research, Experimental Transplantation and Immunology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Methods for Treatment and Diagnosis of Psychiatric Disorders

Mon, 20 Sep 2010 11:00:00 GMT

Current drugs used to treat schizophrenia block dopamine receptors. These drugs can effectively suppress the “positive” symptoms of schizophrenia but have little impact on the debilitating or “negative” symptoms of the disease which include social withdrawal, emotional unresponsiveness, difficulty with attention and memory, and apathy. There is thus a therapeutic need for improved antipsychotics that can improve both positive and negative symptoms. This technology describes novel interactions between neuregulins (NRGs), ErbB receptors, and dopamine signaling pathways that may influence the expression of schizophrenia. Researchers at the NIH demonstrated that NRGs reverse long term potentiation (LTP) when given shortly after LTP is established without affecting basal transmission. Blockade of ErbB receptors with antagonists prevented depotentiation by NRG, and NRG showed no effect in an ErbB-4 knockout mouse model. Thus NRG regulation of LTP occurs through the ErbB-4 receptor. Data also showed that dopamine antagonists block the effects of NRGs on LTP. These findings could be useful in the development of antipsychotic drugs that block NRG actions, and in doing so, provide better therapies for schizophrenia.

This technology describes methods of treating schizophrenia with an antagonist that blocks neuregulin-1 activation of the ErbB-4 receptor signaling pathway, methods of identifying schizophrenia in affected patients, as well as methods of identifying modulators of ErbB-4 receptor signaling. This technology may also be applicable for treating or preventing other psychiatric disorders such as, bipolar disorder, attention deficit disorder (ADD), and autism. CRADA Opportunity: The National Institute of Child Health and Human Development, Section on Molecular Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Fenoterol and Fenoterol Analogues for Treatment of Glioma, Glioblastoma, and Astrocytoma

Thu, 09 Sep 2010 15:00:00 GMT

To date there is no effective treatment for the brain tumors or brain cancers indentified as gliomas, glioblastomas, or astrocytomas.

This technology relates to the discovery that fenoterol and related analogues block astrocytoma and glioblastoma cell division at low doses. In a xenograft model utilizing the 1321N1 astrocytoma tumor implanted in the flank of SKID mice, the (R,R)-4-methoxyfenoterol analogue significantly decreased tumor growth relative to a control group receiving vehicle and studies utilizing [³H]-(R,R)-4-methoxyfenoterol have shown that the compound readily passes the blood-brain barrier. The anti-tumor effect is associated with the ability of fenoterol and related analogues to induce production of cyclic adenosine monophosphate (cAMP), which is normally decreased in glioblastomas and astrocytomas. Induced cAMP production inhibits brain tumor growth in vivo. Fenoterol and related analogues are beta-2 adrenergic receptor (beta2 AR) agonists and the anti-tumor effect is associated with the expression of this receptor. Since there is a heterogeneous expression of beta2 AR in human brain tumors, patients who will respond to fenoterol therapy can be predetermined leading to individualized treatment. In addition to use in the initial treatment of brain tumors, the systemic and CNS bioavailability of the drug after oral administration and the minimal systemic toxicity suggest that fenoterol and it analogs can be used in the adjuvant treatment of patients with beta2 AR-positive gliomas, glioblastomas or astrocytomas. Studies with a number of fenoterol analogs and CNS-implanted tumors are in progress.

The fenoterol analogues discussed in this technology are subject to HHS Ref. No. E-205-2006/3 (U.S. Patent Application No. 12/376,945 and PCT Publication No. WO/2008/022038). CRADA Opportunity: The National Institute on Aging, Laboratory of Clinical Investigation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of fenoterol and fenoterol analogs in the front line and adjuvant treatment of CNS tumors and other beta2 AR expressing tumors. Please contact Nicole Guyton, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information. Click here to view the NIA collaborative opportunity announcement.

Assay for Arf GTP-binding Proteins

Thu, 09 Sep 2010 19:00:00 GMT

The worldwide laboratory research reagents market is expected to surpass $13 billion in 2010, and the field of biotechnology appears key to maintaining the market's growth. Antibodies are becoming increasingly significant, especially for targeting the diseased cells and cell compounds.

Researchers at the National Cancer Institute (NCI), NIH, have developed an antibody-based assay that measures levels of Arf GTP-binding proteins, some of which have been linked to the invasive behavior of cancer cells. The assay is robust, can be performed both on cell lysates and fixed cells, and can distinguish among specific endogenous Arf-GTP isoforms. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cellular and Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Superresolution Microscopy via Azicon Beam Polarization Devices

Tue, 31 Aug 2010 23:00:00 GMT

The technology offered for licensing pertains to novel polarizers that produce tangentially and radially polarized beams. The polarizers and polarizing beam splitter of the technology include one or more pairs of axicons (also known as conical lenses) that are configured to separate an input beam into a radially polarized component and a tangentially (or azimuthally) polarized component. A second axicon pair can be positioned to recombine the tangentially polarized component so as to provide a more uniform beam intensity. The radial polarized component can be reflected or otherwise directed so that one or both the radial and tangential components are available for use. CRADA Opportunity: The NHLBI Laboratory of Molecular Biophysics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Brian Bailey at 301-594-4094 for more information.

Tempol: A Commercially Available Nitroxide as Cancer Therapeutics

Tue, 24 Aug 2010 03:00:00 GMT

The invention is the discovery that a commercially available stable nitroxide, namely TEMPOL can effectively reduce the level of hypoxia-inducible transcription factor (HIF)-2alpha. Elevated HIF-2alpha is associated with clear cell kidney cancer characterized by mutation of the VHL tumor suppressor gene and with many other cancers. Therefore, TEMPOL can potentially be developed into a cancer drug to treat patients with elevated HIF-2alpha, whether due to compromised VHL function or not. CRADA Opportunity: The Center for Cancer Research, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of Tempol to target HIF-2alpha in cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Chimeric Anti-human ROR1 Monoclonal Antibodies

Mon, 23 Aug 2010 07:00:00 GMT

Available for licensing are mouse anti-human receptor tyrosine kinase-like orphan receptor 1 (ROR1) monoclonal antibodies (mAbs). ROR1 is a signature cell surface antigen for B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) cells, two incurable B-cell malignancies that are newly diagnosed in approximately 15,000 and 3,500 patients per year, respectively, in the United States. Currently, there are no therapeutic mAbs that specifically target B-CLL or MCL cells. Anti-ROR1 mAbs may be linked to chemical drugs or biological toxins thus providing cytotoxic delivery to malignant B-cells and not normal cells. Additionally, these antibodies can be fused to radioisotopes and can be used to diagnose B-CLL and MCL malignancies. CRADA Opportunity: The Center for Cancer Research, Experimental Transplantation and Immunology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-ROR1 mAbs, antibody-drug conjugates, radioimmunoconjugates, bispecific antibodies, and other therapeutic or diagnostic modalities. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

System and Method for Producing Nondiffracting Light Sheets that Improves the Performance of Selective Plane Illumination Microscopy (SPIM)

Mon, 23 Aug 2010 11:00:00 GMT

The technology offered for licensing relates to a system and method of producing nondiffracting beams of light that spatially overlap, but do not interfere with each other when intersecting the detection plane of an optical arrangement. The system includes an illumination source (i.e. ultrafast laser) for transmitting a beam of light through the optical arrangement that includes a diffraction grating for diffracting the light beam to produce beams of light having different wavelengths, which are then passed through an annular aperture that transforms the beams of light into nondiffracting beams having different wavelengths. The method can be readily utilized in Selective Plane Illumination Microscopy (SPIM), a system that provides optical sectioning of a sample that is labeled with fluorescent dyes. SPIM can provide quantitative three-dimensional maps of the distribution of a flurophore within the sample with high spatiotemporal resolution and an excellent signal-to-noise ratio. The standard SPIM technique however produces nonuniform axial resolution, which is caused by the diffraction of the laser beam through the sample, causing degradation in the optical sectioning, and forcing a compromise between field of view and axial resolution. Techniques for decoupling field of view and axial resolution have previously utilized nondiffracting beams (e.g. Bessel beams) for sample illumination. The resulting interference from multiple nondiffracting beams degrades the quality of optical sectioning and the quality of the image. The present technology utilizing nondiffracting noninterfering beams is intended to alleviate the problems associated with the currently used SPIM techniques. CRADA Opportunity: The NIBIB Section on High Resolution Optical Imaging is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the nondiffracting Light Sheets for SPIM. Please contact Hari Shroff at 301-435-1995 or hari.shroff@nih.gov for more information.

Method of Producing Immortalized Primary Human Keratinocytes for HPV Investigation, Testing of Therapeutics, and Skin Graft Generation

Mon, 23 Aug 2010 15:00:00 GMT

One of the major limitations of using cultured keratinocytes for research studies is that primary keratinocytes senesce after a few passages. Keratinocytes from specific anatomical sites are also difficult to culture. Scientists at the NIH have demonstrated that primary keratinocytes, from several anatomical sites, when treated with a small-molecule inhibitor of the ROCK protein maintain a proliferative state and become immortal without genetic modification to the cells. Keratinocytes are also the host cells for human papillomaviruses (HPVs) and other viruses and this technology enables the study of those viruses that do not immortalize cells. In addition, this technology may enhance the quantity of material available for skin grafts, as current grafting techniques are limited by the amount of donor material immediately available. Thus, this technology may provide an ideal model environment for producing large quantities of both normal and diseased primary human keratinocytes from small numbers of primary cells from individual hosts or anatomical sites for research purposes, testing of therapeutics, skin graft generation and HPV investigation. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of producing immortalized primary human keratinocytes. Please contact Johanna Schneider, Ph.D. at 301-451-9824 or schneiderjs@niaid.nih.gov for more information.

Novel Drugs for the Treatment of Schizophrenia

Mon, 23 Aug 2010 19:00:00 GMT

Because psychosis and cognitive decline are among the most common debilitating afflictions of humans, the search for new treatments is very important and timely.

Researchers at the NIH have found that genetic variations on the PIK3CD gene are associated with schizophrenia in Caucasian and African American families and can affect normal human cognition functions such as memory, IQ and executive cognition. The inventors have shown that an inhibitor of the phosphatidylinositol 3-kinase p110 delta (PIK3CD) enzyme, which is encoded by the PIK3CD gene, significantly improves a migratory response that is critically impaired in schizophrenic patients. This drug, as well as other PIK3CD inhibitors, could provide effective treatments of psychosis and cognitive decline. CRADA Opportunity: The National Institute of Mental Health Clinical Brain Disorders Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the development of PIK3CD inhibitors for the treatment of CNS disorders including schizophrenia, psychosis, and cognitive deficiency. Please contact Amanda Law at lawa@mail.nih.gov for more information.

Melanocyte Pigmentation or Proliferation with Neuregulin: Compositions and Methods to Treat Skin Disorders, Including Skin Cancer

Tue, 17 Aug 2010 23:00:00 GMT

Human skin pigmentation is regulated by complex and intricate interactions among melanocytes and keratinocytes in the epidermis and fibroblasts in the dermis. A number of factors secreted from keratinocytes and/or from fibroblasts have been shown to be involved in regulating skin pigmentation after UV exposure. NIH investigators have previously demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. Now, using microarray analysis to compare gene expression patterns in 15 different primary dermal fibroblast populations derived from the dorsal trunk skin of three different skin phototypes (I, III and VI), these investigators have identified a number of genes that differ dramatically in expression. One among them, neuregulin 1 (NRG-1), secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting it is one of the major factors determining human skin color. NRG-l was observed to be highly expressed by fibroblasts derived from darker skin. NIH investigators believe that NRG-1 increases the proliferation of human melanocytes via the phosphorylation of Akt. These results suggest a potential role for NRG-1 in regulating constitutive human skin color and perhaps its dysfunction in pigmentary skin diseases. Based on these observations, NIH investigators are currently developing compositions and methods of modulating pigmentation and proliferation of a melanocyte to prevent or treat skin disorders, including skin cancer. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of NRG-1 (or modifiers of its function) to regulate skin pigmentation. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Matrix Metalloproteinase-9 Blade-1 Region Peptides: Use as Cell Migration Modulators

Wed, 18 Aug 2010 03:00:00 GMT

Matrix metalloproteinase-9 (MMP-9) is an enzyme integrally involved in many normal physiological processes that require degradation and remodeling of the extracellular matrix, such as cell migration and invasion, wound repair, bone remodeling, angiogenesis, and embryonic growth. MMP-9 is shown to be involved in the progression of several diseases including many cancers, cardiovascular diseases, CNS diseases, respiratory diseases, and arthritis. In cancer, MMP-9 is thought to promote growth, migration, and spread of cancer cells by catalyzing the degradation of extracellular matrix proteins, releasing bound growth factors, and allowing cancer cells to escape from the primary tumor.

NIH inventors have discovered that specific polypeptides corresponding to Blade-1 region of MMP-9 hemopexin domain can stimulate migration of cells, specifically the migration of cells expressing beta1 integrin. The present technology can be used to develop novel therapeutic candidates for the prevention and treatment of human disease conditions mediated by MMP-9 promoted cell migration, e.g., cancer, inflammation, fibrotic diseases, cardiovascular diseases, CNS diseases, respiratory diseases, angiogenesis and arthritis. CRADA Opportunity: The National Institute of Environmental Health Sciences, Laboratory of Molecular Carcinogenesis, Cell Adhesion Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Elizabeth M. Denholm, Ph.D. at 919-541-0981 or denholme@mail.nih.gov for more information.

Glioblastoma Diagnostics and Therapeutics

Wed, 11 Aug 2010 07:00:00 GMT

Investigators at the NIH have discovered an Anti-TNF Induced Apoptosis (ATIA) protein, which protects cells against apoptosis. ATIA is highly expressed in glioblastoma and astrocytomas and its inhibition results in increased cell sensitivity to TNF-related apoptosis-inducing ligand induced cell death. Hence, ATIA assays may enable clinicians to effectively stratify patients for appropriate treatment. ATIA exists in a soluble form that can be detected in culture medium of ATIA expressing cells indicating it could be used to develop a non-invasive, blood based diagnostic test such as an ELISA. Glioblastomas and astrocytomas can be diagnosed via MRI and CT scans; however, these scans cannot detect tumor type, i.e. glioblastoma vs. medulloblastoma. The investigators found that ATIA is induced in cells under hypoxia conditions. More importantly, knockdown of ATIA in human glioblastoma cells renders cells to apoptosis under hypoxia conditions. Therefore, ATIA is a potential novel therapeutic target for treating human glioblastoma.

Glioblastoma arise from astrocytes, cells that provide neurons structural and metabolic support. Glioblastomas account for twenty percent of primary brain tumors and fifty percent of astrocytomas. These indications are designated as rare diseases as there is an annual 2-3 newly diagnosed cases of glioblastoma per 100,000 people in the United States whereas the astrocytoma incidence rate is 1.22 cases per 100,000 for individuals aged 0-19 years in the United States. CRADA Opportunity: The National Cancer Institute, Cell and Cancer Biology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

N-Methanocarba Adenosine Derivatives and Their Dendrimer Conjugates as A₃ Receptor Agonists

Wed, 11 Aug 2010 11:00:00 GMT

This technology relates to specific (N)-methanocarba adenine nucleosides that have been developed and dendrimers that connect these compounds to create molecules with multiple targets. Dendrimers are essentially repeated molecular branches presenting the core receptor-binding molecules. The compounds synthesized function as agonists and antagonists of a receptor of the G-protein coupled receptor (GPCR) superfamily. In particular, the receptors of interest for this invention include A₃ adenosine receptors and agonists and antagonists of P2Y receptors, such as P2Y₁ and P2Y₁₄.

Dendrimer conjugates may have one or more advantages, such as increased solubility, reduced toxicity, and improved pharmacokinetic properties. They can also be used to connect other types of molecules without affecting the agonist or antagonists properties. For instance, molecules such as those used for imaging or tracing can be added. Dendrimers can also be used to link more than one type of agonist or antagonist to confer multiple functionalities. This technology provides a novel mechanism to treat a number of disorders related to dysregulation of A₃ adenosine receptors. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, Molecular Recognition Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Kenneth Jacobson at kajacobs@helix.nih.gov for more information.

A Novel Scaffold for Multivalent Display of Ligands

Wed, 11 Aug 2010 15:00:00 GMT

Multivalent interactions are important in cell attachment, wound healing and immune responses. Such interactions are associated with cancer metastasis, blood clotting and the generation of antibodies from a vaccination. Mimicking multivalent interactions on a synthetic scaffold is challenging especially when large numbers of ligands (such as 5 or more) need to be displayed. There are numerous synthetic scaffolds that have been developed, but there are significant limitations that remain.

Scientists at the NIH have designed a novel multivalent scaffold that can display anywhere from 1 to 200 ligands. This system allows different types of ligands to be displayed in a controlled, spatially-addressable manner. This system uses peptide nucleic acids (PNAs) containing gamma-substituted side chains. PNAs are synthetic molecules that possess the bases derived from DNA. This invention could revolutionize the way in which multivalent display is used in research as well as help make vaccinations or prevent disease. CRADA Opportunity: The NIDDK Laboratory of Bioorganic Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this novel scaffold or to collaborate on related laboratory interests. Please contact Marguerite J. Miller at 301-496-9003 and/or millermarg@niddk.nih.gov for more information.

Immortalized Human Bronchial Epithelial Cell Line

Fri, 23 Jul 2010 19:00:00 GMT

Normal cells can be cultured in vitro for a limited period of time before they exhibit a "crisis" or senescence, wherein they display abnormal cell morphology and significant reduction or cessation of cell proliferation. Investigators at the National Cancer Institute developed immortalized cell line by isolating bronchial epithelial cells from non-cancerous individuals and subsequent infection with an adenovirus 12-SV40 virus hybrid. Unlike normal cells, the immortalized cells be cultured continuously in vitro in suitable medium and retain features of normal human bronchial epithelial cells, including the absence of invasive behavior in vitro or in vivo. These cells can also be transfected with oncogenes and used as a model for multistage carcinogenesis, or employed to assay a biological or chemical agent's ability to induce differentiation and carcinogenesis as well as test potential chemotherapeutic agents. CRADA Opportunity: The Center for Cancer Research, Laboratory of Human Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Immortalized Human Bronchial Epithelial Cell Line. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Nitroxyl (HNO) Releasing Compounds and Uses Thereof in Treating Diseases

Fri, 23 Jul 2010 23:00:00 GMT

This technology discloses HNO releasing compounds and methods of treating various diseases with such compounds. HNO has recently emerged as a prospective pharmacological agent. Studies of the chemistry of HNO have led to an understanding that HNO is vastly different from nitric oxide (NO), the one-electron oxidation product of HNO. HNO displays unique cardiovascular properties and has been shown to have positive effects in failing hearts without changing heart rate. HNO has also been shown to have beneficial effects in ischemia reperfusion injury. In addition to the cardiovascular effects observed, HNO has shown initial promise in the realm of cancer therapy. HNO has been demonstrated to inhibit a key glycolytic enzyme. Due to the Warburg effect, inhibiting glycolysis is an attractive target for inhibiting tumor proliferation. HNO has recently been shown to inhibit tumor proliferation in mouse xenografts. Additionally, HNO inhibits tumor angiogenesis and induces cancer cell apoptosis. CRADA Opportunity: The Center for Cancer Research, Laboratory of Comparative Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents that generate HNO in physiological media for therapeutic benefit. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Use of Cucurbitacins and Withanolides for the Treatment of Cancer

Sat, 24 Jul 2010 03:00:00 GMT

Certain members of the cucurbitacin and Withanolide family have been identified that can sensitize some tumor cell lines to cell death (apoptosis) on subsequent exposure of the cells to pro-apoptotic receptor agonists (PARAS) of the TRAIL "death receptors". These PARAS include TRAIL itself, and agonist antibodies to two of its receptors death receptor-4 (DR4 or TRAIL-R1) and death receptor 5 (DR5, TRAIL-R2).

The protein TRAIL has a very interesting characteristic that it can preferentially cause death of cancer cells whereas normal non-transformed cells are unaffected. Thus use of TRAIL or agonist antibodies to its so-called "death receptors" has been a current focus in cancer therapy. CRADA Opportunity: The Center for Cancer Research, Laboratory of Experimental Immunology, Cancer Inflammation Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of certain cucurbatacins or withanolides in combination with pro-apoptotic agonists of TRAIL death receptors for cancer therapy. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Software for Accurate Segmentation of Cell Nuclei in Breast Tissue

Fri, 23 Jul 2010 07:00:00 GMT

Automatic segmentation of cell nuclei is critical in several high-throughput cytometry and pathology applications (1), such as spatial analysis of genetic loci by fluorescence in situ hybridization ("FISH"), whereas manual segmentation is laborious (2). Current automated segmentation methods have varying performance in the presence of distortions introduced during sample preparation, non-uniform illumination, clustering of the individual objects of interest (cells or cell nuclei), and seldom assess boundary accuracy.

Researchers at the National Cancer Institute-Frederick, NIH, have developed an automatic algorithm to segment cell nuclei (3) and FISH signals from two-dimensional images of breast tissue. This automated system integrates a series of advanced image processing methods to overcome the delays inherent to current manual methods for segmenting (delineating) individual cell nuclei in tissue samples. The system automatically selects a subset of nuclei that with high likelihood are accurately segmented. This system has been validated using both simulated and actual datasets that have been accurately analyzed by manual methods. The system generalizes to independent analysis of many spatial parameters useful for studying spatial gene positioning in interphase nuclei, and potentially has a wide range of diagnostic pathology, cytological and high throughput screening applications. CRADA Opportunity: The inventers, working for the Office of the Director, National Cancer Institute, are seeking statements of capability or interest from parties interested in collaborative research (using the Cooperative Research and Development Agreement (CRADA) or Material Transfer Agreement (MTA)) to further develop, evaluate, or commercialize the software for accurate segmentation of cell nuclei and FISH signals in tissue sections. Collaborators working in the field of quantitative and automated pathology may be interested. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Software System with Applications in Clinical Prognosis, Personalized Medicine and Clinical Research

Fri, 23 Jul 2010 11:00:00 GMT

Available for licensing is software that can provide prognostic information for different diseases and in particular for cancer. The software can determine whether a particular genotype has a significant association with survival time for an individual receiving treatment. For example, it can determine if a specific genetic pattern is associated with an increased or decreased time to recurrence of a particular type of cancer for patients on a given treatment regimen. CRADA Opportunity: The NCI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Treatments for Smith-Lemli-Opitz Syndrome and Other Disorders of Cholesterol Biosynthesis

Mon, 12 Jul 2010 15:00:00 GMT

This technology provides methods for treating Smith-Lemli-Opitz Syndrome and other disorders of cholesterol biosynthesis.

Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder caused by an inborn error of cholesterol biosynthesis. It affects an estimated one in 20,000 to 60,000 newborns, and is most prevalent in Caucasians of Central European ancestry. It is characterized by distinctive facial features, microcephaly, mental retardation or learning disabilities, and behavioral problems, as well as malformations in many parts of the body, such as the heart, lungs, kidneys, gastrointestinal tract, and genitalia. However, the clinical manifestations of this disease can vary widely, ranging from relatively moderate symptoms to profoundly severe and life-threatening symptoms. At least 95% of SLOS patients present with some degree of mental retardation and learning disability.

Biochemically, SLOS is caused by disruption of the DHCR7 gene, which is responsible for the final step in the production of cholesterol; this results in low cholesterol levels and an accumulation of toxic byproducts of cholesterol biosynthesis in the blood, nervous system, and other tissues. Supplementary dietary cholesterol is provided to SLOS patients, but is often of limited clinical benefit; because levels of byproducts remain high, they may interfere with the uptake of free cholesterol.

Although some of the behavioral and learning problems are due to developmental problems, a portion of these symptoms are likely due to a biochemical disturbance. That biochemical disturbance is potentially treatable.

In their recent work, the inventors have discovered that the accumulation in SLOS cells of the cholesterol precursor 7-DHC causes abnormal sphingolipid storage and transport, resulting in a cellular phenotype similar to that observed in the lysosomal storage disease Niemann-Pick type C (NPC). They have also discovered that treatment with inhibitors of sphingolipid biosynthesis corrects these abnormalities, and thus such inhibitors are of potential therapeutic benefit for the treatment of SLOS, as well as for other diseases exhibiting similar defects in sphingolipid trafficking.

This technology claims compounds that inhibit sphingolipid biosynthesis for use in treating diseases which have a secondary Niemann-Pick type C disease-like cellular phenotype, including SLOS, as well as methods of treatment and pharmaceutical compositions. CRADA Opportunity: The National Institute of Child Health and Human Development, Section on Molecular Dysmorphology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information. Click here to view the NICHD collaborative opportunity announcement.

Novel Antigen for Use as Vaccine Against Nematode Infection

Mon, 12 Jul 2010 19:00:00 GMT

This invention describes a new vaccine against Strongyoides stercoralis, which establishes a parasitic infection that affects an estimated 100-200 million people worldwide. The potential for fatal disease associated with S. stercoralis infection and the difficulty in treating hyperinfection underscores the need for prophylactic vaccines against the disease. This vaccine uses S. stercoralis immunoreactive antigen (SsIR); a novel antigen capable of providing 70-90 % protection for mice immunized with the antigen. In addition, sera from immunized mice have also been used to effectively protect naive mice from infection.

The invention may also have potential use in diminishing allergic responses, as Strongyoides stercoralis infection has been shown to reduce the murine response to allergens. Consequently, SsIR may be used to immunize individuals and reduce the allergic response. The antigen may also be used to identify homologous antigens from other parasitic nematodes that may be important for vaccine development. CRADA Opportunity: The Laboratory of Parasitic Diseases at NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Thomas Nutman, PhD at tnutman@niaid.nih.gov or Johanna Schneider, PhD at schneiderjs@niaid.nih.gov for more information.

A Transgenic Model of Human Basal Triple Negative Breast Cancer [C3(l)-tag mice]

Mon, 12 Jul 2010 23:00:00 GMT

Basal triple-negative breast cancer (TNBC) is a common form of human breast cancer for which there are no specific, targeted therapies, unlike hormone-responsive or Her2+ breast cancers. TNBC has a much worse prognosis than hormone receptor + cancer and is disproportionately high in the African-American population. NIH scientists have created and characterized a transgenic model that is currently an excellent mouse model for TNBC that shares important molecular characteristics of human TNBC, making it highly useful for preclinical testing of drugs and novel therapies. This model may provide a valuable means of identifying new drugs and therapies that could be translated to human clinical trials. The mouse model also develops prostate intraepithelial neoplasia and prostate cancer, therefore has also been used for studies of prostate cancer. The studies using the mouse model may fill important public health service needs. CRADA Opportunity: The Transgenic Oncogenesis and Genomics Section of the Laboratory of Cancer Biology and Genetics, Center for Cancer Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this mouse model of TNBC to study cancer biology and for preclinical testing. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Use of Immunosuppressive Agents for Treatment of Age-related Macular Degeneration (AMD) and Diabetic Retinopathy

Tue, 13 Jul 2010 03:00:00 GMT

AMD belongs to a group of disorders in which the immune system may play an important role. This invention discloses that patients with AMD gain additional therapeutic benefit from combination treatment of immunosuppressive agents and standard-of-care in comparison to standard-of-care alone. This invention slows the progression of choroidal neovascularization (CNV) and may have implications for related pathologies, including diabetic retinopathy. Clinical data from a small, randomized pilot clinical trial are available. CRADA Opportunity: The National Eye Institute, Laboratory of Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of immunosuppressive agents in the treatment of age related macular degeneration. This is in light of new findings that immune mechanisms appear to be central to the expression of the clinical disease we know as AMD. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Human Single-domain Antibodies (dAbs) Against Insulin-like Growth Factor 1 Receptor (IGF-1R) and Its Ligands

Fri, 02 Jul 2010 07:00:00 GMT

Insulin-like growth factor (IGF) mediated signaling has been implicated in the development of several epithelial cancers, such as prostate, breast, and colorectal cancers. This technology consists of human single domain antibodies (dAbs) that bind to human insulin-like growth factor 1 receptor (IGF-1R) or its ligands, IGF-1 and IGF-2. These dAbs are comprised of only a single variable domain of an antibody with a human framework and three complementarity determining regions (CDRs). Several of these antibodies inhibit the IGF signaling pathway so they may be therapeutic candidates for the treatment of IGF-related cancers. CRADA Opportunity: The Center for Cancer Research Nanobiology Program (CCRNP), National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the dAbs that exhibit potent inhibitory activities against the human IGF signaling pathway. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Identification of Cancer Stem Cells

Fri, 02 Jul 2010 11:00:00 GMT

Cancer stem cells (CSC) are thought to be responsible for cancer initiation, maintenance, and therapeutic failure. A hallmark of stem cells is self-renewal via asymmetric cell division (ACD) into daughter stem-cells and cells predestined for differentiation. Demonstration of fundamental stem-cell's traits such as ACD in cancers is lacking. Label retaining cells are thought to be enriched for stem-like cells. Label retaining cells are thought to be the results of either very slow cycling cells and/ or cells undergoing ACD. This invention is directed to the identification, isolation and purification of cancer stem cells by detecting asymmetrically dividing cells and/ or label retaining cells. Detection of asymmetric cell division via non-random chromosomal cosegregation (ACD-NRCC) in various human cancers defines a unique and novel class of universal cancer stem cells, and potentially suggests a novel mechanism of carcinogenesis. The isolation of CSC might be used as a basis for a potential new strategy in cancer therapeutics. The invention also might have some implications in genetics and regenerative medicine. CRADA Opportunity: The Center for Cancer Research, Surgery Branch, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize our unique method for isolating cancer stem cells. We are seeking interested parties who would be interested in collaboration with the goal of developing cancer stem cell cell-lines for personalized targeted therapies, drug testing and finding novel targets for cancer treatments. In addition, we would like to collaborate with parties interested in developing normal (not cancer) adult tissue stem-cell cell-lines for adult tissue regeneration such as Parkinson's disease, liver failure, Alzheimer, etc. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

A New Class of Antibiotics: Naturally-occurring Chrysophaetins and Their Analogues

Mon, 21 Jun 2010 15:00:00 GMT

This invention, offered for licensing and commercial development, relates to a new class of naturally occurring antimicrobial compounds called Chrysophaetins, and to their synthetic analogues. Isolated from an alga species, the mechanism of action of these compounds is through the inhibition of bacterial cytoskeletal protein FtsZ, an enzyme necessary for the replication of bacteria. FtsZ is responsible for Z-ring assembly in bacteria, which leads to bacterial cell division. Highly conserved among all bacteria, FtsZ is a very attractive antimicrobial target.

The chrysophaetin exhibits antimicrobial activity against drug resistant bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), as well as other drug susceptible strains. The general structure of the natural compound is shown below:

The inventors are working on a synthetic route for the compound and analogs. They have made progress and now have two halves of the molecule. These will be further dimerized to produce a synthetic chrysophaentin. It is expected that the analogues will show similar antimicrobial activity to the natural products and will utilize the same mechanism of action.

The market potential for the disclosed compounds is huge ($24 billion in 2008) due to the very limited number of new antibiotics developed in recent decades and the increased epidemic of infectious diseases. In fact, infectious diseases are the leading cause of death worldwide. In the United States alone, more people die from MRSA than from HIV (Journal of the American Medical Association, 2007) and more than 90,000 people die each year from hospital acquired bacterial infections (Centers for Disease Control). A development of new drugs with distinct mechanism of action and efficacy against resistant bacterial strains may therefore be commercially attractive. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the chrysophaentin antibiotics. Please contact Marguerite J. Miller at 301-451-3636 or millermarg@niddk.nih.gov for more information.

A Highly Sensitive ELISA for Detection of Serum Levels of Soluble IL-15 Receptor Alpha

Tue, 01 Jun 2010 19:00:00 GMT

The invention is an ELISA based assay that can be used in the clinical setting to detect the presence of soluble human IL-15 receptor (IL-15R) in the serum or plasma.

Interleukin-15 (IL-15), a cytokine has potential as an immunotherapeutic agent for cancer treatment because it is a critical factor for the proliferation and activation of natural killer (NK) and CD8+ T-cells.

In addition to studies directed toward augmenting IL-15 action to increase patient immune responses to their tumor, IL-15R alpha play a pathogenic role in leukemia and autoimmune disorders. IL-15 and IL-15R alpha are coexpressed in association with a number of autoimmune disorders including rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, chronic liver disease, and refractory celiac syndrome including that disease associated with the development of enteropathy associated CD8 T-cell lymphoma. An assay for the released serum form of IL-15R alpha is required to evaluate these IL-15R alpha inducing agents. CRADA Opportunity: The Center for Cancer Research, Metabolism Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Parkin and PINK1-Based Therapies for Parkinson's Disease and Other Mitochondrial Diseases

Tue, 01 Jun 2010 23:00:00 GMT

This technology provides methods for treating Parkinson's disease and other diseases associated with mitochondrial dysfunction.

Mutations in mitochondrial DNA (mtDNA) are responsible for a broad spectrum of inherited diseases, with symptoms that can range from mild to very severe. Accumulated mutations in mtDNA have also been linked to the pathogenesis of common diseases such as cancer, diabetes mellitus, and neurodegenerative disorders. In Parkinson's disease, for example, the accumulation of defective mitochondria appears to be responsible for the loss of midbrain neurons that produce dopamine neurotransmitter, which is a key feature of this disease.

In their recent work, Dr. Richard Youle and co-investigators have linked the fields of mitochondrial quality control and the genetics of Parkinson's disease. They have discovered that the Parkin protein is selectively recruited to damaged mitochondria, and promotes autophagic degradation of these mitochondria; ablation of Parkin increases levels of damaged mitochondria in cells. They have also discovered that another protein associated with mitochondrial disease, the mitochondrial PTEN-induced kinase-1 (PINK1), accumulates on the surface on damaged mitochondria, and that the presence of full-length PINK1 is necessary and sufficient for Parkin recruitment to the mitochondria. Thus, both Parkin and PINK1 play specific and important roles in mitochondrial quality control and disposal.

This technology describes methods of treating Parkinson's disease or other mitochondrial diseases such as KSS (Kearns Sayre syndrome), MERRF (Myoclonus epilepsy ragged-red fibers), MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), NARP (Neuropathy ataxia, retinitis pigmentosa), and LHON (Leber hereditary optic neuropathy) by increasing PINK1 or Parkin expression or activity, as well as methods of reducing the number of defective mitochondria in a cell by increasing PINK1 or Parkin expression or activity. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of treating mitochondrial diseases by increasing PINK1 or Parkin expression or activity. Please contact Dr. Martha Lubet at 301-435-3120 or lubetm@mail.nih.gov for more information.

Improving the Therapeutic Effectiveness of Foreign Proteins

Wed, 02 Jun 2010 03:00:00 GMT

Foreign proteins are recognized by the immune system, which typically responds by creating neutralizing antibodies to the foreign protein. While this is helpful in response to an infection or the administration of a vaccine, it is troublesome when foreign proteins are administered for the treatment of disease in a non-vaccine capacity (e.g., an immunotoxin, therapeutic antibody, protein replacement therapy, etc.). These neutralizing antibodies decrease the therapeutic effectiveness of the protein, ultimately resulting in the inability to administer the foreign protein to a patient with any benefit. Thus, if a particular disease requires multiple administrations, the chance of achieving a successful response with the foreign protein becomes unlikely.

A particular instance where neutralizing antibodies have reduced therapeutic effectiveness is the use of immunotoxins for treatment of cancer. Immunotoxins comprise an antibody domain for targeting a surface antigen on a cancer cell and a toxin domain that is capable of killing the targeted cell. The toxin domain is typically a modified form of a bacterial toxin, such as Pseudomonas exotoxin A, and is therefore recognized as a foreign protein by the patient's immune system. Although immunotoxins have an initial therapeutic effect, the effectiveness is ultimately mitigated by neutralizing antibodies against the toxin domain of the immunotoxin. Thus there is a clear need to reduce the formation of neutralizing antibodies in patients who are administered a foreign protein like an immunotoxin.

This technology addresses this need by reducing the formation of neutralizing antibodies through the co-administration of the immunosuppressive agent CP-690,550 with a therapeutic foreign protein. Specifically, the inventors found that co-administering CP-690,550 and an immunotoxin to a mouse model reduced the production of neutralizing antibodies to the immunotoxin. These results suggest that the use of CP-690,550 in combination with any foreign protein therapeutic could allow multiple cycles of therapy and result in improved therapeutic efficacy. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Software System for Analysis of Extremely Large Experimental Dataset and Multidimensional Drug Discovery

Tue, 01 Jun 2010 07:00:00 GMT

This invention is a computer software suite that will enable its user to investigate extremely large experimental datasets in a simple yet multidimensional manner. The software, Omnimorph, allows multidimensional investigation of any form of data including experimental datasets in biomedical science using either gene arrays or proteomics. Omnimorph allows the user to look for extremely subtle correlated differences between experimental datasets which will allow the investigator to discover far more drug- or disease-specific factors than other analytical methods currently used. The software of present invention has been employed in the targeted discovery of G protein-independent receptor-based pharmacotherapeutics. These discoveries represent an entirely new GPCR-based G protein-independent pharmacopeia. Therefore, the Omnimorph is not only newly developed software, but the Omnimorph suite can also be used as a simple and unbiased tool to detect novel and unexpected modes of GPCR-based drug actions. This could potentially alter the way drugs are developed and screened in the future. CRADA Opportunity: The National Institute on Aging, Laboratory of Neurosciences-Receptor Pharmacology Unit, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Vio Conley at 301-435-2031 or conleyv@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Delivery of Transthyretin (TTR) across the Blood Brain Barrier as a Treatment for Alzheimer's Disease

Wed, 26 May 2010 11:00:00 GMT

The invention describes products and methods of treating Alzheimer's disease. Alzheimer's disease is characterized by the formation of amyloid plaques and tangles in areas of the brain critical for learning and memory. The products are a transthyretin and other blood brain barrier impermeable proteins transformed into blood brain barrier permeable forms by the coupling of an Inter-Cellular Adhesion Molecule-1 (ICAM-1) targeting agent. Transthyretin binds to, and inhibits amyloid protein from forming plaque deposits. Deposition of amyloid is thought to underlie the disease pathology of Alzheimer's. Thus, this invention treats Alzheimer's by inhibiting the formation of amyloid plaques, which normally would result in amyloid plaque formation, inflammation, and neuronal cell death. CRADA Opportunity: The NIH Chemical Genomics Center (NCGC) is open to collaborating in order to further develop this invention. Please contact Dr. Juan Marugan at maruganj@mail.nih.gov for more information about collaborative research opportunities.

UOK171, A Spontaneous Clear Cell Type Renal Cell Carcinoma (ccRCC) Human Cell Line Derived from a Surgically Removed Tumor

Wed, 26 May 2010 15:00:00 GMT

Scientists at the National Institutes of Health (NIH) have developed a renal cell carcinoma (RCC) cell line designated UOK171 from the resected tumor of a patient diagnosed with stage IV high nuclear grade clear cell type renal cell carcinoma (ccRCC). The UOK171 cell line was immortalized spontaneously by mincing the resected tumor into pieces followed by propagation of the cells over more than twenty generations. One of the most prominent characteristics of this cell line is its intact, nonmutated von Hippel-Lindau (VHL) tumor suppressor gene. In the majority of sporadic and hereditary ccRCC cases, the VHL gene is functionally disrupted due to hypermethylation or the gene is completely lost. Thus, the UOK171 cell line is very useful as a positive control for VHL gene expression in studies of the genetic and molecular mechanisms underlying advanced ccRCC, a disease for which there is no effective treatment. Specifically, this cell line has been used as a non-methylated control cell line in studying the effects of 5-Aza-dCyd and Zebularine on VHL re-expression from methylated-VHL cell line models. These agents do not affect the methylation status of the VHL gene in UOK171. This cell line also exhibits decreased fibroblast growth factor 5 (FGF5) expression, unbalanced chromosome 3 translocations, translocations involving chromosome 14, the losses of chromosome 14 and 22, and chromosome structural aberration 1(8) (q10). UOK171 is also one of the 40-member cell lines in the National Cancer Institute (NCI) Urologic Oncology Branch (UOB) Tumor Cell Line Repository. CRADA Opportunity: The Urologic Oncology Branch, Center for Cancer Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize UOK171. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

888-mel: A Target for Anti-Tumor Immune Responses

Wed, 26 May 2010 19:00:00 GMT

Scientists at the National Institutes of Health (NIH) have developed a human melanoma cell line designated 888-mel from the resected tumor of a 26-year old Caucasian female (patient 888) diagnosed with metastatic melanoma, a frequently terminal cancer. The 888-mel cell line was derived from three separate subcutaneous melanoma lesions on the patient and possesses many characteristics representative of melanoma cell lines developed by these researchers. Most prominently, the 888-mel cell line was used to develop a tumor infiltrating lymphocyte (TIL) culture with high affinity for the tumor cells of patient 888. When the TIL 888 culture was provided as an autologous adoptive immunotherapy treatment to patient 888 in combination with interleukin-2 (IL-2), a complete remission of subcutaneous, lung, and mucosal metastases was observed in the patient for over three years.

Since this medical breakthrough, the 888-mel cell line has been well characterized through various laboratory procedures and data involving this cell line has been published as part of numerous articles. Studies have shown that the cell line expresses a variety of tumor associated antigens (TAAs), including tyrosinase, TRP1, TRP2, gp100, MART-1, p15, gp75, mutated beta-catenin, and p53. However, 888-mel does not normally express the MAGE 1, 2, or 3 TAAs. Many melanoma cell lines are HLA-A2 restricted, but the 888-mel cell line is HLA-A2 negative. The HLA class I typing for this cell line is as follows: HLA-A0101, A2402, B55, B62, Cw5201, Cw55, DRbl*1502, DRbl*1610, DQbl*0601, DRb5*0102, DRb5*0203. 888-mel is a validated source of HLA class I peptides utilized in screens that test the reactivity of TIL cultures that are candidates for adoptive immunotherapy trials. 888-mel is also a standard cell line for studying immune responses in cancer, particularly T cell responses. Other experiments show that roscovitine, a cyclin-dependent kinase inhibitor, can induce apoptosis in the 888-mel cell line, so these cells may be useful in various cell death studies. CRADA Opportunity: The Surgery Branch, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to carry out genotypic as well as phenotypic analysis of the 888 mel cell line in order to better understand the nature of tumor cells that respond to therapy. In addition, this cell line can be used as a target of humoral or cell mediated immune responses as a part of studies characterizing the nature of immune responses directed against tumor cells. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Software System for Processing and Analysis of Multi-dimensional NMR Data

Fri, 21 May 2010 23:00:00 GMT

Available for licensing is a software system useful in applications involving nuclear magnetic resonance (NMR). The software system, called NMRPipe, is written in the C programming language, and makes use of the TCL/TK scripting environment. The system includes over 500 modules for processing and analyzing experimental data of one to four dimensions collected on NMR spectrometers. The system exploits the UNIX computer operating system facilities of pipelines and scripts to link modules in a highly flexible, user-definable manner. NMR is a widely used analytical method, applied to both solution and solid state samples. The information obtained from such data pertains to the structure, motion, and interactions of molecular systems, including proteins, nucleic acids, and organic molecules. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the NMRPipe software system. Please contact Cindy Fuchs at 301-451-3636 or Frank Delaglio at frankde@niddk.nih.gov for more information.

Simple, Quantitative and Highly Specific Antibody Detection of Lyme Disease

Sat, 22 May 2010 03:00:00 GMT

This invention uses the Luciferase Immunoprecipitation System (LIPS) as a highly specific and high throughput method for diagnosing Borrelia burgdorferi (Bb) infection, a causative agent of Lyme disease. Many antigens, fused to the renilla luciferase (RUC) system, were tested for their ability to detect the disease; however, a novel synthetic protein called VOLVO displayed the highest sensitivity and specificity of those tested. VOLVO demonstrated 94% sensitivity and 100% specificity and markedly out-performed the C6 ELISA test (currently the most sensitive test available, with 76% sensitivity and 98% specificity) in an analysis of independent validation serum sets. Unlike the C6 ELISA, the VOVO LIPS assay displayed a wide dynamic range of antibody detection spanning over a 10,000-fold range without serum dilution. These results indicate that LIPS screening method using VOVO or other Bb antigens offer a more convenient, efficient and quantitative approach to serological screening of antibodies to Lyme disease.

The VOVO LIPS test may benefit from a large market as it could potentially become part of a routine screening panel for Lyme disease. In addition to its high sensitivity and specificity, the test also provides a rapid, simple and high-through-put approach for efficient screening of the disease. It may also be adapted for detection of Borrelia species endemic to other regions of the world. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Laboratory of Sensory Biology, Neurobiology and Pain Therapeutics Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov.

The First Birt-Hogg-Dubé Tumor Cell Line and Wild Type Folliculin-restored Renal Cell Line as In Vitro and In Vivo Models

Fri, 21 May 2010 07:00:00 GMT

Scientists at the National Institutes of Health (NIH) have developed a novel renal cell carcinoma (RCC) cell line designated UOK257, which was derived from the surgical kidney tissue of a patient with hereditary Birt-Hogg-Dubé (BHD) syndrome and companion cell line UOK257-2 in which folliculin (FLCN) expression has been restored by lentivirus infection. These cell lines harbors a germline mutation of FLCN gene (alias BHD) and displays loss of heterozygosity, can grow as xenograft in nude mice. Patients affected with BHD develop skin papules (fibrofolliculomas), lung cysts, spontaneous pneumothorax and an increased risk for bilateral multifocal renal tumors. Loss of both copies of the FLCN gene has been documented in BHD renal tumors; however, the molecular mechanisms by which inactivation of the encoded protein, folliculin, leads to the BHD phenotype are currently unknown. They have developed an important research tool for in vitro folliculin functional studies. The companion cell line will be extremely useful for comparative biochemical analyses of cell culture systems in which the FLCN gene is either expressed or inactivated, including identification of renal tumor biomarkers, alteration of biochemical pathways resulting from loss of FLCN function, tumorigenicity of FLCN null versus FLCN restored cells, preclinical therapeutic drug testing in xenograft animal models produced from injection of these cell lines, etc. UOK 257 and UOK257-2 are thus useful cell models for studying the underlying molecular derangements associated with mTOR pathways and other biogenesis pathways in human kidney cancer and for evaluating novel therapeutic approaches for this disease. UOK257 is also one of the 40-member renal cancer cell lines in the Tumor Cell Line Repository of the Urologic Oncology Branch (UOB), National Cancer Institute (NCI). CRADA Opportunity: The Center for Cancer Research, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize kidney cancer tumor cell lines as described in above abstract through MTA, CRADAs, CTAs, BML, etc.:

For laboratory interests on the basis of metazoan tumor cell survival, including growth factor-regulated nutrient uptake; glucose or glutamine metabolism and epigenetic gene control; tumor cell bioenergetics and cell growth through AMPK and mTOR signaling pathways.
In vitro and in vivo cell model for BHD cancer syndrome. It is voluble research tool for laboratory interested in identification of new BHD tumor antigens for immunotherapy.
These paired cell lines for FLCN gene expression and function studies, including gene therapy, cytogenetics, gene mutation research, and examination abnormalities of interaction with other proteins that may contribute to BHD.
The excellent in vivo model for preclinical xenograft imaging, including stable transfection. Cells could be labeled with reagents for PET, Luciferase, Fluorescent, for transgenic mice, optical molecular imaging, etc., and provides useful platform for preclinical drug evaluations.

Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Parvovirus B19 Codon Optimized Structural Proteins for Vaccine and Diagnostic Applications

Thu, 06 May 2010 11:00:00 GMT

Parvovirus B19 (B19V) is the only known pathogenic human parvovirus. Infection by this viral pathogen can cause transient aplastic crisis in individuals with high red cell turnover, pure red cell aplasia in immunosuppressed patients, and hydrops fetalis during pregnancy. In children, B19V most commonly causes erythema infectiosum, or fifth's disease. Infection can also cause arthropathy and arthralgia. The virus is very erythrotropic, targeting human erythroid (red blood) progenitors found in the blood, bone marrow, and fetal liver. Currently, there are no approved vaccines or antiviral drugs for the treatment or prevention of B19V infection.

The subject technology is a series of plasmid constructs with codon optimized B19 viral capsid genes (VP1 and VP2) that can be expressed in mammalian cells. Transfection of vectors encoding these optimized VP1 and VP2 genes into different mammalian cell lines, including 293, Cos7, and Hela cells produce virus-like particles (VLPs). The vectors include bicistronic plasmids expressing the VP1 and VP2 proteins at different ratios to produce B19V VLPs with optimal antigenicity for vaccine applications. This technology can also be used for diagnostic applications and development of a viral packaging system for producing infectious B19V virus. CRADA Opportunity: The National Heart Lung and Blood Institute, Hematology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the subject technology. Please contact Cecilia Pazman, Ph.D., at pazmance@mail.nih.gov for more information.

Erythroid Progenitor Cell Line for Hematological Disease Applications

Wed, 05 May 2010 15:00:00 GMT

Plasmodium vivax (malaria) is a significant health concern in many parts of Asia, Latin America, North Africa, and the Middle East. There is a lack of continuous culture systems for this pathogen. The subject technology is an erythroid progenitor continuous cell line (termed CD36E) identified by erythroid markers CD36, CD33, CD44, CD71, CD235, and globoside. These CD36E cells are heterozygous for Fya and Fyb (Duffy antigen). Due to recent evidence that Plasmodium vivax (P. vivax) can infect erythroid progenitor cells (reference: YX Ru et al. and T Panichakul et al.), these cells can be potentially used for culturing P. vivax and other species of malaria. This in turn could aid development of malaria related treatments and/or products. In addition, the cell line can also be used for other hematological disease applications that involve red blood cells or red blood cell precursors. The CD36E cells also produce alpha, beta, and chi hemoglobin and therefore may be used for research involving hemoglobin. CRADA Opportunity: The National Heart Lung and Blood Institute, Hematology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the CD36E cell line. Please contact Cecilia Pazman, Ph.D., at pazmance@mail.nih.gov for more information.

Laser Scanning Microscopy for Three Dimensional Motion Tracking for Volumetric Data

Tue, 27 Apr 2010 19:00:00 GMT

The technology offered for licensing and for further development is in the field of volumetric tissue scanning microscopy. More specifically, the invention provides for a device, system and methods that can acquire and analyze volumetric data from a high-speed laser-scanning microscope and compute motion of the sample under the microscope in three dimensions. This computed motion is used to adjust position of the sample in real time to maintain field of view and relative location. This motion compensation scheme can be used to collect micron-scale information over time, which can be important in a number of research or medical device applications. CRADA Opportunity: The National Heart, Lung, and Blood Institute, Laboratory of Cardiac Energetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize automatic 3D volumetric motion tracking systems for use during in vivo microscopy. Please contact Denise Crooks, Ph.D. at 301-435-0103 or crooksd@nhlbi.nih.gov for more information.

A Method of Measuring Ultraviolet A (UVA) Protection in Sunscreen Products

Tue, 27 Apr 2010 23:00:00 GMT

There are different types of ultraviolet (UV) rays in sunlight. UVB radiation causes redness (erythema) or sunburn. While UVA radiation, which absorbs deep into the skin, causes more long-term effects such as wrinkles, skin aging and skin cancer.

Effective sunscreens are expected to block both UVA and UVB radiation. The Sun Protection Factor (SPF) label found on all over-the-counter sunscreen products is a better measure for UVB protection than UVA protection. Currently, there is no standard in vivo test to determine the amount of UVA protection in sunscreen products, despite the fact that many products are advertised as effectively blocking both UVA and UVB radiation.

This invention describes sets of genes useful for measuring UVA exposure in human skin and assessing sunscreen products for their ability to block UVA radiation. CRADA Opportunity: The Center for Cancer Research, Dermatology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Retroviral Vectors for Selective Reversible Immortalization of Stimulus-responding Primary Cells

Wed, 28 Apr 2010 03:00:00 GMT

Researchers at the National Cancer Institute-Frederick, NIH, have developed a novel set of retroviral vectors and producer cell lines useful for selective reversible immortalization of primary cells (i.e. lymphocytes) that respond to a stimulus, such as a viral antigen (e.g. HIV toxoids), a tumor antigen, or a growth factor.

Derived from the murine leukemia virus (MuLV), these retroviral vectors will only infect dividing cells. Therefore, only primary cells activated by the stimulus will be infected and immortalized, thereby creating an "antigen-specific trap."

The primary cells to be immortalized can be in targeted tissue or in stimulated ex vivo culture. The transduced cells can be expanded to large numbers without differentiating, and returned to the primary cell stage by removal of the introduced genes using a vector excision strategy. CRADA Opportunity: The Center for Cancer Research, AIDS and Cancer Virus Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Fully-human Monoclonal Antibodies Against Human EphrinB2 and EphB4 for Use in the Study of Cancer Pathogenesis

Tue, 20 Apr 2010 07:00:00 GMT

Ephrin receptor tyrosine kinases and their ephrin ligands have been implicated in cancer pathogenesis. Ephrin receptors and ligands affect tumor growth, invasiveness, angiogenesis, and metastasis. Ephrin signaling activities in cancer are complex and are only now beginning to be uncovered.

Researchers at the National Cancer Institute-Frederick, NIH, have developed a set of five fully-human monoclonal antibodies against human Ephrin-B2 and Ephrin type-B receptor 4 ("EphB4"). The antibodies were identified by screening a naïve human antibody phage display library against Ephrin-B2 and EphB4. These human monoclonal antibodies have high affinity and specificity for Ephrin-B2 and EphB4. CRADA Opportunity: The Center for Cancer Research Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

15kD Granulysin for Monocyte Differentiation: A New Immunotherapeutic for Both in vivo and ex vivo Applications

Tue, 20 Apr 2010 11:00:00 GMT

Granulysin is a cytolytic and proinflammatory molecule expressed by activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. It has been implicated in many of diseases including infection, cancer, transplantation, autoimmunity, skin and reproductive maladies. Small synthetic forms of granulysin are being developed as novel antibiotics and studies suggest that granulysin may be a useful diagnostic biomarker and/or therapeutic for a wide variety of diseases.

The invention relates to methods of stimulating or enhancing an immune response using 15 kD granulysin. Investigators at the NIH have discovered that 15 kD granulysin (but not 9 kD granulysin) activates monocytes and induces them to differentiate into mature dendritic cells and activates allospecific T cells. This activation and subsequent differentiation induced by 15 kD granulysin may prove important in inducing or regulating immune responses in a host. Consequently, this invention could be used treat tumors and infections, particularly as an adjuvant for vaccines and immunotherapies. Further, this technology could be used to treat autoimmune disorders and organ transplant rejection. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cellular and Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3131 or hewesj@mail.nih.gov for more information.

Thermostable Y-Family Polymerases From Fungi for Use in Forensic DNA Services and Analysis of Damaged or Ancient DNA

Tue, 20 Apr 2010 15:00:00 GMT

Y-family polymerases are able to bypass lesions in DNA that would otherwise block replication by high fidelity DNA polymerases and are key to the effective study of ancient DNA and for use in forensic medicine. These enzymes are ubiquitous and are found in all kingdoms of life: bacteria, archaea and eukaryotes. The number of proteins related to the Y-family polymerases is well over 200 orthologs and despite being closely related at the phylogenetic level, the few polymerases now characterized, each show a unique set of properties including processivity, fidelity, and the ability to bypass certain types of DNA. Y-family polymerases from thermostable organisms are of particular interest because the enzymes isolated from such species tend to be more stable, easy to work with and may have more utility in assays at higher temperatures, such as Polymerase Chain Reaction (PCR). For example, the thermostable archeal Sulfolobus solfataricus DinB-like polymerase Dpo4 can bypass lesions by generally inserting the correct complementary nucleotide opposite a variety of damaged bases and can, under appropriate conditions substitute for Taq polymerase in PCR applications [Nucleic Acids Res. 2001 Nov 15;29(22):4607-4616; HHS Ref. No. E-232-2001/0]. Additionally, functional and structural organization of this family of polymerases permits domain swapping designed to optimize specific properties of use in novel applications [J Biol Chem. 2004 Jul 30;279(31):32932-32940].

Dr. Woodgate's group at the National Institute of Child Health and Development have expanded their earlier work (HHS Ref. Nos. E-166-2004/0, /1, & / 2) and have now cloned and expressed full length Y-family polymerases Thermoascus auranticus Pol eta, Thermomyces lanuginosus Pol eta, Thermomyces lanuginosus Pol iota, Thermomyces lanuginosus Pol kappa, Thermomyces lanuginosus REV1, Sporotrichum thermophile Pol eta, Sporotrichum thermophile Pol iota, Sporotrichum thermophile Pol kappa, and Sporotrichum thermophile REV1. These full length enzymes may be a good substitute for Taq polymerase in applications utilizing fluorescent nucleoside triphosphate derivatives. These lesion-bypassing polymerases could also be included along with a conventional thermostable polymerase in a PCR protocol designed to amplify old or damaged DNA samples which could greatly increase recoverability, accuracy and length of products. Other applications could include labelling or tagging DNA, real-time PCR, detection of SNPs, mismatches or DNA lesions, mutagenic PCR, directed-evolution methods and expanding the "DNA alphabet" utilizing non-natural nucleotides.

Available for licensing are several full length novel Y-family polymerases. These enzymes and methods should be of interest to forensic DNA service companies as well as to research reagent companies pursuing novel thermophilic enzymes for use in ancient and damaged DNA analysis and for novel applications with modified nucleotides. CRADA Opportunity: The National Institute of Child Health and Human Development, Laboratory of Genomic Integrity, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the aforementioned thermostable fungal Y-family DNA polymerases. Please contact Joseph Conrad, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information. Click here to view the NICHD collaborative opportunity announcement.

Nontypeable Haemophilus Influenzae Lipooligosaccharide Based Conjugate Vaccines for the Prevention of Otitis Media and Respiratory Infections

Tue, 20 Apr 2010 19:00:00 GMT

Nontypeable Haemophilus influenzae is one of the leading causative agents of otitis media in children and accounts for 11% of pneumonia cases in children. This is due in part to the current immunizations of children with Streptococcus pneumoniae polysaccharide and conjugate vaccines to prevent otitis media. The proportion of otitis media caused by pneumococcal strains covered by the vaccines have decreased while those caused by nontypeable Haemophilus influenzae have significantly increased. At some point during early childhood, otitis media affects more than 80% of children under 6 years of age. Otitis media can lead to deafness and language or learning deficits. In adults, nontypeable Haemophilus influenzae causes respiratory tract infections primarily in persons with chronic obstructive pulmonary disease, one of the most common lung diseases. Exacerbation of chronic obstructive pulmonary disease in the elderly is the fourth leading cause of death in the United States. Otitis media can be treated with antibiotics; however, the emergence of antibiotic resistance makes vaccines against nontypeable Haemophilus influenzae an attractive alternative to those classes of drugs. The current Haemophilus influenzae type b conjugate vaccines have no protective effect against nontypeable strains.

The technologies described herein are conjugate vaccines against nontypeable Haemophilus influenzae. The vaccines are comprised of lipooligosaccharides (LOS) from which esterified fatty acids have been removed from lipid A to form detoxified LOS conjugated to an immunogenic carrier such as tetanus toxoid, and an adjuvant such as alum. In vivo data in the Chinchilla animal model are available. The vaccines can be potentially used as a component in a combination vaccine with other pediatric vaccine components. CRADA Opportunity: The National Institute on Deafness and Other Communication Disorders, Vaccine Research Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the subject technology. Please contact Brian W. Bailey, Ph.D. at 301-594-4094 or bbailey@mail.nih.gov for more information.

Moraxella Catarrhalis Lipooligosaccharide Based Conjugate Vaccines for the Prevention of Otitis Media and Respiratory Infections

Tue, 20 Apr 2010 23:00:00 GMT

Moraxella catarrhalis is one of the three leading causative agents of otitis media in children. This is due in part to the current immunizations of children with Streptococcus pneumoniae polysaccharide and conjugate vaccines to prevent otitis media. The proportion of otitis media caused by pneumococcal strains covered by the vaccines have decreased while those caused by Moraxella catarrhalis and nontypeable Haemophilus influenzae have significantly increased. At some point during early childhood, otitis media affects more than 80% of children under 6 years of age. Otitis media can lead to deafness and language or learning deficits. In adults, Moraxella catarrhalis is a major cause of bronchopneumonia and exacerbation of existing chronic obstructive pulmonary disease for chronic heavy smokers or elderly patients with chronic pulmonary disease. Moraxella catarrhalis infections can be treated with antimicrobial agents; however, the emergence of antibiotic resistance makes vaccines against Moraxella catarrhalis an attractive alternative to antimicrobial drugs. There are currently no Moraxella catarrhalis vaccines on the market.

The subject technologies are conjugate vaccines against Moraxella catarrhalis. The vaccines are comprised of isolated lipooligosaccharides (LOS) from which esterified fatty acids have been removed to produce detoxified LOS or from which lipid A has been removed to produced a detoxified oligosaccharide (OS) covalently linked to an immunogenic carrier such as tetanus toxoid, and adjuvants such as alum. The vaccines can potentially be used as a vaccine component in a combination vaccine containing other pediatric vaccine components. CRADA Opportunity: The National Institute on Deafness and Other Communication Disorders, Vaccine Research Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the subject technology. Please contact Brian W. Bailey, Ph.D. at 301-594-4094 or bbailey@mail.nih.gov for more information.

A Method of Reducing Cholesterol Biosynthesis with Specific MicroRNAs

Wed, 21 Apr 2010 03:00:00 GMT

This technology is directed to the discovery of specific microRNAs that target and downregulate enzymes within the cholesterol biosynthetic pathway and is currently being tested in vivo.

Briefly, microRNAs regulate the translation of messenger RNAs (mRNAs) into protein. The inventors have discovered a set of specific microRNAs that downregulate the expression of multiple enzymes in the cholesterol biosynthetic pathway. Importantly, this technology may provide the benefits of cholesterol lowering therapies to patients that are not suited for statin-based treatments. Statins block the cholesterol biosynthetic pathway at a single enzymatic step and may result in the deleterious build-up of a metabolic intermediate. In contrast, this technology simultaneously targets the expression of multiple enzymes required for cholesterol biosynthesis and thus may avoid the build-up of metabolic intermediates. The reduction of cholesterol biosynthesis has been indicated for improved cardiovascular health and lowers the risk for heart disease, heart attack, and stroke. CRADA Opportunity: The National Heart, Lung and Blood Institute, Pulmonary Vascular Medicine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize microRNA regulation of the cholesterol biosynthetic pathway. Please contact Dr. Denise M. Crooks at 301-435-0103, crooksd@nhlbi.nih.gov for more information.

New Mouse Strain with Conditional Deletion of SMAD7: Analysis of Disease Processes Involving Immunological, Fibrotic or Cardiovascular Indications

Tue, 20 Apr 2010 07:00:00 GMT

SMAD7 conditional knockout mice are available for licensing. SMAD7 can be knocked out by breeding with CRE-recombinase transgenic mice with a variety of promoters to yield tissue or cell type-specific deletions of SMAD7. SMAD7 has been shown to play a role in bone morphogenesis, cardiovascular tissue generation, immune regulation and fibrosis. Therefore, these mice provide a unique model to examine the role of the SMAD7 gene in disease processes that involve immunological, fibrotic, or cardiovascular components. Specifically, these mice may represent a novel model of Scleroderma, a disease with both an immunological and fibrotic component. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Elizabeth M. Denholm, denholme@niehs.nih.gov, for more information.

Topical Formulation of Histone Deacetylase (HDAC) Inhibitors: Treatments for Cancer and Immunological Skin Disorders

Tue, 20 Apr 2010 11:00:00 GMT

This technology relates to topical formulations of Histone Deacetylase (HDAC) inhibitors (HDIs) that can be used to treat cancers such as cutaneous T-cell lymphoma (CTCL) and skin disorders such as lupus, contact dermatitis, and drug eruptions which are associated with malignant or autoreactive lymphocytes from the immune system. HDIs, such as depsipeptide, have been demonstrated to be effective against CTCL when administered internally but a topical preparation may be more useful for treatment at earlier stages of the disease.

HDIs are molecules that inhibit the activity of a group of enzymes that remove small chemical groups called acetyl groups from many different proteins, including proteins that regulate gene expression. By altering the acetylation of these proteins, HDAC inhibitors can induce tumor cell differentiation, cell cycle arrest, and cell death. A variety of chemically distinct molecules exhibit HDAC inhibitory activity and their potential as therapeutics for cancer and other indications is being investigated. The HDI depsipeptide is a cyclical peptide derived from a bacterium and is indicated as a second line treatment for CTCL through intravenous administration. Development of a topical preparation of depsipeptide and/or other HDAC inhibitors may help reduce their toxicity and increase their effectiveness in treating CTCL, other cancers, as well as other diseases. CRADA Opportunity: The Center for Cancer Research, Medical Oncology Branch and Affiliates, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize topical therapy using HDIs. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Composite Probes and Use Thereof in Super Resolution Microscopy

Tue, 20 Apr 2010 15:00:00 GMT

The technology offered for licensing and for further development is in the field of fluorescence microscopy. More specifically, the invention describes and claims the composite probes for super resolution optical techniques using super resolution via transiently activated quenchers (STAQ). The composite probes include a donor moiety and an acceptor moiety joined by a linker. The acceptor moiety, when excited by incident radiation, is excited to a state which, for example, absorbs in the donor emission region, such that the acceptor moiety in its excited state quenches at least a portion of the donor moiety emission. Other transiently activated quenching mechanisms and moieties could accomplish the same task by reducing donor population. Also disclosed are methods for irradiating a selected region of a target material including the composite probe, wherein the composite probe enables improved resolution by point spread function modification. CRADA Opportunity: The National Heart, Lung and Blood Institute (NHLBI) Laboratory of Molecular Biophysics (LMB) is also seeking statements of capability or interest from parties interested in collaborative partnerships to further develop, evaluate, or commercialize this technology. Please contact Brian Bailey, Ph.D. at bbailey@mail.nih.gov for more information.

Peroxidase and Peroxidase Substrate Peptides (PSPs) for Treatment of Inflammatory Disorders and Allergies

Tue, 20 Apr 2010 19:00:00 GMT

NIH investigators have identified an unexpected and previously unrecognized function of the peroxidase/dual oxidase system in protecting the mucosal surfaces, such as in the gastrointestinal and respiratory tracts. Specifically, NIH investigators have shown that a peroxidase and a dual oxidase (Duox) form a dityrosine network that decreases gut permeability to immune elicitors and prevents activation of epithelial immunity in An. gambiae mosquitoes. This technology provides for novel compositions that enhance the formation of a dityrosine network on epithelial cells, such as those found in the gastrointestinal and respiratory tract mucosa of vertebrates, by forming a mucosal barrier on the epithelial surface preventing or inhibiting epithelial cell-mediated inflammatory responses (such as those associated with an inflammatory disease or an allergic reaction). Exemplary compositions include a mammalian or plant heme peroxidase and a peroxidase substrate peptide (PSP).

The compositions of this technology can be useful as therapeutics for several diseases or disorders involving epithelial cell-mediated inflammatory responses (e.g., inflammatory bowel diseases such as Crohn's, and allergic disorders). CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Office of Technology Development, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Peroxidase and Peroxidase Substrate Peptides (PSPs) for Treatment of Inflammatory Disorders and Allergies. Please contact Dana Hsu at 301-496-2644 for more information.

Use of Modified Peptide Nucleic Acids for Visualizing DNA

Thu, 25 Mar 2010 23:00:00 GMT

The compounds described in this technology may be useful in the development of nucleic acid detection kits for various pathogens.

Technologies for genomic detection most commonly use DNA probes to hybridize to target sequences, and require the use of Polymerase Chain Reaction (PCR) to amplify target sequences. Replacing the DNA probe with peptide nucleic acid (PNA) can greatly eliminate the need for PCR because the binding strength of PNAs to complementary DNA is stronger than DNA binding to complementary DNA. In addition, PNAs are nuclease and protease resistant, and form very stable and highly sequence-specific complexes with DNA.

This technology describes a method of making pure enantiomers of trans-tert-butyl-2-aminocyclopentylcarbamate (tcycp) and methods of modifying PNAs by incorporating tcycp compounds into the PNA. This technology may also be practical for detecting infectious agents such as anthrax, avian flu, tuberculosis (TB), severe acute respiratory syndrome (SARS), human papilloma virus (HPV) and human immunodeficiency virus (HIV). CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, Drug-Receptor Interactions Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Daniel Appella at appellad@niddk.nih.gov for more information.

Novel Compositions for Use as Bone Scaffolds and Enhancers of Bone Regeneration

Fri, 26 Mar 2010 03:00:00 GMT

This invention is directed to the discovery that a mixture of an organic polymer and inorganic particles may hold therapeutic utility as a biomaterial for artificial bone scaffolds, injectable bone-filling materials, and enhancement of new bone generation. This composition has demonstrated utility in vivo in mice.

The inventors have discovered a means of producing a stably homogenous mixture of the organic polymer and inorganic particles by crosslinking the two components. In contrast to current technologies, this invention not only imparts sufficient mechanical and load-bearing strength but also provides a suitable environment for new bone formation. Importantly, since the chemical reaction applied to make this biomaterial does not produce any harmful molecules or heat, it can be used in an injectable form. Bone formation or replacement is often a desired therapy for bone loss or defects due to fractures or bone degenerative diseases. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Craniofacial and Skeletal Diseases Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

Radioprotectants and Tumor Radiosensitizers Targeting Thrombospondin-1 and CD47

Thu, 25 Mar 2010 07:00:00 GMT

Radiation therapy not only damages cancer cells, but it also damages healthy cells and can cause serious side effects for patients. One effort to enhance the therapeutic potential of radiotherapy, while reducing its detrimental effects on normal tissue and maintaining tumor sensitivity, is centered upon the development of radioprotective agents.

NIH inventors previously discovered that when the secreted protein, thrombospondin-1 (TSP1) binds to its receptor CD47, this signaling pathway prevents nitric oxide from dilating blood vessels and increasing blood flow to organs and tissues. They found that blocking TSP1-CD47 interaction through the use of antisense morpholino oligonucleotides, peptides or antibodies has several therapeutic benefits; one of them being increased blood flow to ischemic tissues.

In the present technology, the inventors discovered that hindlimb irradiated TSP1 and CD47 null mice have less hair loss, and decreased cell death in muscle and bone marrow than untreated TSP1 and CD47 null mice. They also discovered that when irradiated human vascular cells are treated with antibodies towards TSP1 or CD47, viability and proliferative capacity are preserved. Furthermore, the inventors determined that irradiation of wild type mice following treatment with CD47 antisense morpholino resulted in decreased apoptosis in irradiated tissues at 24 hours, preservation of hematopoietic stem cell proliferative capacity in irradiated bone marrow, and less alopecia, ulceration, and desquamation at the end of eight weeks. These results led the inventors to propose that antagonists of TSP1 and/or CD47 preserve cell viability and tissue function following radiation treatment, and these antagonists may be useful as radioprotective agents to reduce side effects associated with radiation therapy. Remarkably, the same treatment dramatically enhanced the delay in melanoma and squamous carcinoma tumor regrowth following irradiation. Thus, these agents are radioprotective agents for normal tissue but radiosensitizers for tumor tissue.

The present technology describes the use of morpholinos, peptides and antibodies that block the TSP1/CD47 signaling pathway as radioprotectants for normal tissue, radioenhancers for tumor tissue, and methods of selectively protecting normal tissue from damage caused by radiation exposure by contacting the tissue with these agents. CRADA Opportunity: The Center for Cancer Research, Laboratory of Pathology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize CD47-targeting agents as radioprotectants and tumor sensitizers. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Zscan4, a Therapeutic Target for Cancer, Regenerative Medicine and Aging

Wed, 24 Mar 2010 11:00:00 GMT

This technology has broad potential for the development of therapeutics for cancer, diseases of aging, and regenerative medicine, and targets Zscan4, a gene that regulates telomere length and genomic stability in embryonic stem (ES) cells.

The ability to maintain genomic stability in ES cells and other stem cells is critical for the development of stem cell-based therapies; genomic stability and telomere length are also active areas of cancer and aging research. NIA investigators have discovered that the Zscan4 gene regulates telomere length and genomic stability in ES cells, and plays an essential role in early embryonic development; this activity is independent of telomerase activity. The investigators have shown that ablation of Zscan4 results in shortened telomere length and deterioration of the karyotype of ES cells, and that Zscan4 overexpression increases telomere length.

This technology discloses methods for increasing genome stability or increasing telomere length in an ES cell, and methods of treating a subject in need of ES cell therapy. Also disclosed are methods of promoting blastocyst outgrowth of embryonic stem cells, as well as Zscan4 expression vectors and methods of identifying stem cells expressing Zscan4. CRADA Opportunity: The National Institute on Aging, Laboratory of Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Nicole Guyton, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information.

Long Acting Ophthalmic Analgesic Eye Drops

Tue, 23 Mar 2010 15:00:00 GMT

This invention is directed to the discovery that resiniferatoxin (RTX) produces a three to four day analgesic effect when topically applied to the cornea. Efficacy for RTX as an effective analgesic has been demonstrated in vivo in rats. Importantly, unlike currently available analgesics, RTX left the blink reflex intact and did not impact mechanical sensitivity. RTX also did not impair epithelial wound healing and functioned without detectable damage to the cornea.

RTX is a potent agonist of the transient receptor potential channel, subfamily V, member 1 (TRPV1). TRPV1 is involved in pain sensation and is expressed only in select neurons. Unlike other local analgesics that target a wide breadth of neurons, RTX targets only those neurons that express TRPV1, leaving the important blink reflex and mechanical sensitivity of the eye unaffected. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Laboratory of Sensory Biology, Neurobiology and Pain Therapeutics Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

mFPR2 Transgenic and Knockout Mouse Models for Alzheimer's and Other Inflammatory Diseases

Fri, 19 Mar 2010 19:00:00 GMT

Human Formyl Peptide-Like Receptor 1 (hFPLR1) has been implicated in host defense for disease processes including Alzheimer's disease, infection, and other inflammatory diseases. hFPLR1 and its mouse homologue Formyl Peptide Receptor 2 (mFPR2) are G-protein coupled receptors that are expressed at high levels on phagocytic leukocytes, mediating leukocyte chemotaxis and activation in response to a number of pathogen- and host-derived peptides. Activation of hFPRL1/mFPR2 by lipoxin A4 may play a role in preventing and resolving inflammation. Also, hFPRL1/mFPR2 has been shown to mediate the chemotactic activity of amyloid beta 1-42, a key pathogenic peptide in Alzheimer's disease.

Available for licensing are mice expressing the mFPR2 transgene on either the FVB or C58BL background, as well as mFPR2 knockout mice on the C57BL background. These mice are anticipated to be highly useful in the study of a wide variety of inflammatory, infectious, immunologic and neurodegenerative diseases. CRADA Opportunity: The National Cancer Institute - Frederick, Laboratory of Molecular Immunoregulation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize mFPR2 Transgenic and Knockout Mouse Models for Alzheimer's and Other Inflammatory Diseases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Polarization Adapter for Colposcope

Wed, 17 Mar 2010 23:00:00 GMT

The invention offered for licensing is directed to a polarization adaptor for colposcopes. The colposcope is a medical diagnostic device that examines an illuminated magnified view of a patient's cervical, vaginal, and vulva tissues during a colposcopy procedure. Specifically, the invention provides for a specialized polarized camera (polarization adaptor) for integration into commercially available colposcopes. The addition of polarization to currently available colposcope results in an enhanced image video output that allows the user to view hidden subsurface tissue structures and textures, thereby allowing for better diagnosis of pathological conditions.

The device which can readily be adapted to commercial colposcope enables the separation of specularly reflected light from diffusely backscattered light, coming from deeper tissue layers. In combination with suggested data processing algorithm, based on correlation analysis, this allows one to enhance imaging of the hidden subsurface tissue structure (texture). CRADA Opportunity: The Eunice Shriver National Institute of Child Health and Human Development, Section on Analytical and Functional Biophotonics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the polarization camera for cervical tissue characterization. Please contact Joseph Conrad, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

A New Transmission Blocking Vaccine for Leishmania Infection

Thu, 18 Mar 2010 03:00:00 GMT

A novel transmission blocking vaccine has been developed that can eliminate or reduce the number of Leishmania chagasi parasites in the gut of the sand fly species, Lutzomyia longipalpis. The vaccine involves the production of antibodies to the sand fly midgut protein, LP1, which is normally expressed in the midgut of the sand fly during a blood meal. This vaccine could potentially block parasite transmission from the sand fly to mammalian hosts and significantly reduce the incidence of leishmaniasis in endemic areas of the world such as Brazil, India, and Indonesia where leishmaniasis accounts for over 58,000 deaths annually.

Studies have shown that LP1 antibodies produced by immunized mice are able to reduce the number of L. chagasi parasites that develop in the midgut of Lu. longipalpis. These results illustrate the potential use of the protein as a vaccine to immunize dogs and protect humans from visceral leishmaniasis transmitted by the sand flies that feed on the infected, vaccinated dogs. In endemic areas such as Brazil where dogs are the principal reservoir for L. chagasi, the LPl antigen alone or in combination with other sand fly midgut proteins could be used to immunize household pets and stray dogs. Vaccinated dogs will produce antibodies to LPl, and once a sand fly feeds on blood from the infected and vaccinated dogs, the antibodies will inhibit development of the parasite in the gut of the sand fly. This approach can effectively block Leishmania transmission to human hosts. Such vaccines have the potential to reduce the risk of humans acquiring leishmaniasis without the risks involved in human vaccination. CRADA Opportunity: The NIAID, OTD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "A New Transmission Blocking Vaccine for Leishmania Infection". Please contact Dana Hsu at 301-496-2400 for more information.

Novel Regulatory B cells for Treatment of Cancer and Autoimmune Disease

Wed, 17 Mar 2010 07:00:00 GMT

The manner by which cancers evade the immune response is not well-understood. What is known is that the manner is an active process that regulates immune responses employing at least two types of suppressive cells, myeloid-derived suppressive cells and regulatory T cells (Tregs), a key subset of CD4⁺ T cells that controls peripheral tolerance to self- and allo-antigens. Tregs are considered to play a key role in the escape of cancer cells from anti-tumor effector T cells.

Cancer cells have been found to directly activate resting B cells to form suppressive regulatory B cells (tBregs) and utilize them to evade immune surveillance and mediate metastasis. tBregs directly inhibit CD4⁺ and CD8⁺ T cell activity in a cell contact-dependent manner, induce FoxP3⁺ T cell activity, and promote Treg-dependent metastasis.

Researchers from the National Institute on Aging (NIA), NIH, have developed methods for the generation of tBregs, and for using tBregs to produce Tregs, and methods that inactivate or deplete tBregs. These methods have significant therapeutic value in the combat with cancer immune escape and metastasis, and in the control of harmful autoimmune diseases. CRADA Opportunity: The Immunotherapeutics Unit, National Institute on Aging, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the utilization of regulatory B cells to control autoimmune diseases and strategies that inactivate tBregs to control cancer immune escape. Please contact Nicole Darack, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Akt-Ser473 Phosphorylation as a Marker for Predicting Taxane Chemotherapy Outcome

Thu, 11 Mar 2010 12:00:00 GMT

Over the past decades, taxanes such as paclitaxel and docetaxel have emerged as effective chemotherapy agents for breast cancer and other malignancies. Taxanes are effective in many patients, however, not all patients benefit from this type of chemotherapy. A significant need remains for a means of predicting clinical outcome from taxane-based chemotherapy.

Akt, a serine/threonine kinase that can block apoptosis, has been implicated in the regulation of microtubule dynamics and organization. Akt phosphorylation and its transducing downstream events play a central role in cell survival and cell cycle progression at the G2/M transition. Paclitaxel or docetaxel inhibits Akt-Ser473 phosphorylation (pAkt) and induces mitotic arrest. Therefore, taxanes may cause more damage to tumor cells that are dependent on pAkt for survival and cell cycle progression, significantly impacting treatment outcome.

Researchers at the National Cancer Institute, NIH, have identified pAkt as having predictive significance for paclitaxel chemotherapy outcome in patients with early stage breast cancer. The researchers have developed an immunohistochemistry method for determining pAkt status with appropriate controls for assay performance and cutoff for pAkt positivity. They also discovered methods of correlating pAkt expression with clinical outcome (disease-free survival and overall survival). pAkt is a novel predictive marker of taxane chemotherapy, and can be applied to indicate which patients should receive taxane-based chemotherapy. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the pAkt assay for use in a clinical setting. The National Cancer Institute would be particularly interested in discussing collaborations to provide additional clinical validation of pAkt as a primary biomarker. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Tumor Tissues Harboring Mutations in cAMP-specific Phosphodiesterases Useful for the Study of Endocrine Tumors

Thu, 11 Mar 2010 17:00:00 GMT

Researchers at the National Institute of Child Health and Human Development (NICHD), NIH, have made available samples of patient-derived adrenal and heart tumors that harbor genetic mutations that have been implicated in the predisposition of endocrine tumors. An endocrine tumor is a growth that affects the parts of the body that secrete hormones. Because an endocrine tumor arises from cells that produce hormones, the tumor itself can produce hormones and cause serious illness.

The tumor samples made available herein contain deletions in the cyclic nucleotide phosphodiesterase (PDE) PDE7A or PDE8B genes that impair PDE function and are characterized by high sensitivity to changes in cAMP levels. Commercially, phosphodiesterase inhibitors are widely used in the treatment of various disorders, including asthma, pulmonary hypertension, and erectile dysfunction, suggesting a potential utility for these tissues in a wide range of investigations. CRADA Opportunity: The National Institute of Child Health and Human Development, Division of Intramural Research, is seeking statements of capability or interest from parties interested in collaborative research. Please contact Joseph Conrad, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Spontaneously Transformed Mouse Epithelial Cancer Cell Lines Serving as Mouse Models: A New Model for Cancer Research

Thu, 11 Mar 2010 22:00:00 GMT

Investigators at the NIH have created a collection of 45 mouse epithelial cancer cell lines derived from six organs: bladder, cervix, colon, lung, kidney, and mammary glands. These cell lines were obtained from spontaneously transformed primary cell cultures without genetic, viral or chemical manipulation so they can serve as mouse models for studying the natural process of oncogenesis.

The cell lines were characterized cytogenetically during their transformation from normal to spontaneously immortalization and were found to recapitulate many of the changes observed in human cancer cells such as the deregulation of oncogenes (Myc, Mdm2) and tumor suppressor genes (Cdnk4a/Ink4a/p16, Rb).

Carcinomas that arise from the epithelial cells lining organs lead to the most common cancers in humans. However, research on cellular transformation has largely relied on fibroblast cells which are not of epithelial origin and therefore, may not reflect the changes that lead to epithelial oncogenesis. The availability of these mouse epithelial cancer cell lines should allow for a more accurate analysis of this process. CRADA Opportunity: The National Cancer Institute, Cancer Genetics Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Defensin-Based Therapeutics for the Treatment of Pulmonary Disease

Fri, 12 Mar 2010 03:00:00 GMT

Investigators at the National Heart, Lung and Blood Institute have developed modified defensins that are resistant to degradation, have improved characteristics compared to unmodified defensins, and are promising candidates for pulmonary disease therapeutics.

Defensins are small cationic peptides that defend the lung against pathogenic microorganisms and play an important role in innate immunity. However, during lung inflammation, defensin concentrations can reach levels that are cytotoxic for airway epithelial cells. Therefore, the development of methods to produce modified defensins that exhibit reduced cytotoxicity, while retaining the ability to stimulate the innate immune response, would be of potential therapeutic benefit for pulmonary diseases.

The inventors have previously shown that a defensin, human neutrophil peptide 1 (HNP-1), is elevated in samples from the lungs of patients with inflammatory lung disease, and that the HNP-1 in these samples is ADP-ribosylated at one or both of two arginine residues within the protein. In vitro studies by the inventors show that ADP-ribosyl-HNP-1 has reduced cytotoxic activity compared to HNP-1, while retaining its T cell chemotactic properties and ability to promote neutrophil recruitment, and thus ADP-ribosyl-HNP-1 may play an important role as a regulator of the inflammatory response. These properties would also be useful for treatment of pulmonary inflammation and lung diseases. However, ADP-ribosylated HNP-1 and other defensins are degraded rapidly in vivo due to the susceptibility of the ADP-ribose moiety to attack by hydrolases and pyrophosphatases, which limits their therapeutic potential.

The inventors have recently discovered that the ADP-ribosylated arginine residues in HNP-1 can be converted to ornithine through a non-enzymatic process that results in a peptide with an altered pharmacological profile. The investigators have also successfully generated ornithine-substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 in vitro, which are currently being characterized. Thus, ornithine-substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 may be promising candidates for the development of therapeutics to treat pulmonary disease, and the strategy of replacing ADP-ribosylated residues with ornithine to enhance stability and therapeutic efficacy may also be extended to other defensins.

Through an earlier, related invention, the inventors have also demonstrated that recombinant proteins wherein tryptophan or phenylalanine residues substitute for ADP-ribosylarginine have a similar stabilizing impact on polypeptides, making them more suitable as therapeutic agents.

The inventors also hypothesize that it would be possible to develop a treatment that increases levels of an ADP-ribosylated therapeutic protein, such as HNP-1, in the lung via inhalation administration of the therapeutic protein in conjunction with nicotinamide adenine dinucleotide (NAD), which is required for ADP-ribosylation. This could represent a unique therapeutic strategy for treating pulmonary disease. CRADA Opportunity: The National Heart, Lung and Blood Institute Translational Medicine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize defensin-based therapeutic agents to treat pulmonary diseases. Please contact Brian W. Bailey, Ph.D. at 301-494-4094 or bbailey@mail.nih.gov for more information.

Caspase Inhibitors Useful for the Study of Autoimmune or Inflammatory Diseases

Thu, 11 Mar 2010 08:00:00 GMT

Novel and potent caspase 1 inhibitors are available for licensing. In particular, this technology discloses potent and selective caspase 1 inhibitors that target the active site of the enzyme. Caspase 1 is known to play a pro-inflammatory role in numerous autoimmune and inflammatory diseases and therefore represents an excellent target for treatment of a broad range of diseases, including but not limited to Huntington's, amyotrophic lateral sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. Not surprisingly this enormous potential has resulted in at least three caspase 1 inhibitors entering clinical trials (VX-740, IDN-6556, and VX-765) in recent years. CRADA Opportunity: The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/299,790. Please contact Dr. Craig J. Thomas via e-mail (craigt@nhgri.nih.gov) for more information.

Conditional V2 Vasopressin Receptor Mutant Mice as a Model to Study X-linked Nephrogenic Diabetes Insipidus (XNDI)

Mon, 01 Mar 2010 13:00:00 GMT

X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. This technology provides a unique and viable animal model of XNDI. NIH investigators have generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin.

Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology. These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, Molecular Signalling Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Jurgen Wess at jwess@helix.nih.gov for more information.

A Biomarker and Therapeutic Target for Ovarian Cancer

Mon, 01 Mar 2010 18:00:00 GMT

This technology provides methods of diagnosing or treating certain ovarian cancers using STAMP, a steroid cofactor. There are currently no effective methods for early-stage diagnosis of ovarian cancer. Diagnosis is usually made through a combination of physical examination, ultrasound imaging, and a blood test for the tumor marker CA-125. The CA-125 test only returns a true positive result for about 50% of early-stage ovarian cancers, and may be elevated in other conditions not related to cancer, so it is not an adequate early detection tool when used alone.

The inventors have shown that STAMP mRNA levels are elevated in ovarian cancer samples, including early-stage cancers. They have also found that in a subset of ovarian cancer cell lines, introduction of STAMP siRNAs slows cell proliferation. These findings suggest that STAMP may be useful as a biomarker to detect early stage cancer in ovarian tissues, and is also promising as a therapeutic target for a subset of ovarian cancers. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Steroid Hormones Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize STAMP, a steroid cofactor. Please contact Dr. S. Stoney Simons at steroids@helix.nih.gov for more information.

Diagnosis and Treatment of Cancer Using Histone Deacetylase Inhibitors and Radiolabeled Metaiodobenzylguanidine

Mon, 01 Mar 2010 23:00:00 GMT

Pheochromocytoma is a neuroendocrine tumor of the adrenal glands. Pheochromocytoma patients display the signs and symptoms of those of sympathetic nervous system hyperactivity. Up to 36% of patients worldwide with pheochromocytoma develop metastatic disease and have a 5-year survival rate of approximately 50% after diagnosis. Patients with metastatic pheochromocytoma exhibit excessive levels of circulating catecholamines, which results in increased risk of strokes, cardiac arrhythmias, and hypertensive complications. Current treatments for malignant pheochromocytoma include targeted radiation using [¹³¹I]-metaiodobenzylguanidine ([¹³¹I]-MIBG), cytotoxic chemotherapy, octreotide, tumor hemoembolization, etc. The success of these treatments varies based on the sites and growth rate of metastatic lesions.

The present invention provides a method for treating a mammalian tumor with a histone deacetylase inhibitor (HDACi), and followed by administering [¹³¹I]-MIBG. Methods of diagnosis and imaging of mammalian tumors are also disclosed. These findings suggest that HDACi could enhance the therapeutic efficacy of [¹³¹I]-MIBG treatment in patients with malignant pheochromocytoma. CRADA Opportunity: The National Institute of Child Health and Human Development, Reproductive Biology and Adult Endocrinology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize [¹³¹I]-MIBG treatment of malignant/metastatic pheochromocytoma, paraganglioma, and neuroblastoma; also [^123/131I]-MIBG scintigraphy - in all situations histone deacetylase to be used before MIBG is used. Please contact Joseph Conrad, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information. Click here to view the NICHD collaborative opportunity announcement.

BODIPY®-FL Nilotinib (Tasigna®) for Use in Cancer Research

Tue, 02 Mar 2010 04:00:00 GMT

Investigators at the National Institutes of Health have produced a fluorescently labeled derivative of the clinically-approved, tyrosine kinase inhibitor (TKI) nilotinib (Tasigna®) for use in research. This was accomplished by conjugating the fluorescent dye BODIPY®-FL to nilotinib.

The TKI imatinib (Gleevec®) is the first targeted therapeutic developed and is used as first line treatment of Philadelphia chromosome-positive (Ph+) cancers like chronic myeloid leukemia (CML). Although imatinib is highly effective, after continued use the cancer cells frequently become resistant to the drug. Nilotinib is a second generation TKI developed to overcome imatinib resistance, but eventually it can also result in drug resistance.

The fluorescent nilotinib conjugate was developed to study the mechanism by which cancer cells become resistant to nilotinib and better understand its cytotoxic effects. CRADA Opportunity: The National Cancer Institute, Transport Biochemistry Section, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize bodipy conjugated tyrosine kinase inhibitors that are currently used in the clinic for the treatment of CML or gastric cancers. We are also interested in evaluating third generation tyrosine kinase inhibitor derivatives as modulators of ABC drug transporters to improve the efficiency of chemotherapy in animal (mouse) model system. In addition, we can identify possible pharmacokinetic interactions of the novel kinase inhibitors with ABC drug transporters. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Diagnostic Biomarker of Metastasis for Improved Clinical Management of Head and Neck Cancer

Mon, 01 Mar 2010 09:00:00 GMT

Squamous Cell Carcinoma of the Head and Neck (HNSCC) is associated with poor prognosis due to the advanced stage of disease (metastasis) typically found at the time of diagnosis. Investigators at the NIH have developed a sensitive method using a protein biomarker for detecting even just a few HNSCC tumor cells in lymph nodes with occult disease. Combination of this staging technique with intraoperative sentinel lymph node mapping would improve the management of HNSCC by identifying patients for which radical lymph node dissection is most appropriate, sparing those for which it is not, and informing decisions for adjuvant cancer therapy during a single surgery.

This technology arose from the discovery that the Desmoglein-3 (DSG3) protein which is highly expressed in tumors of squamous epithelial origin, like HNSCC, is also expressed in invaded lymph nodes but it is not found in normal lymph nodes. Therefore, DSG3 can serve as a biomarker for detecting metastastatic spread of squamous cell carcinoma tumors. This is achieved by performing protein detection immunoassays to samples (biopsy, aspirate, or isolated cells) of suspect lymph nodes. CRADA Opportunity: The NIDCR, OPCB, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of DSG3 as a biomarker for detecting metastastatic spread of squamous cell carcinoma tumors. Please contact David W. Bradley, Ph.D. at bradleyda@nidcr.nih.gov for more information.

Novel Kinase Inhibitors Targeting the PH Domain of AKT for Preventing and Treating Cancer

Mon, 01 Mar 2010 14:00:00 GMT

Activation of the PI3K/Akt signaling pathway has been implicated in the development of cancer. Akt, a kinase that is central to this pathway, is found at elevated levels in many tumors and is associated with a poor disease prognosis. Many research studies have validated Akt as a therapeutic target for the development of anti-cancer drugs. Most efforts of drug development targeting Akt have focused on inhibitors of the ATP-binding domain which tend to interfere with other physiologically important kinases. An alternative strategy that has been proposed to improve drug specificity is the targeting of the unique pleckstrin homology (PH) domain of Akt.

Investigators at the National Institutes of Health have screened a library of small chemical compounds with drug-like characteristics that likely bound to the PH domain and have identified several candidates previously unknown to interact with Akt. These compounds were tested and found to inhibit Akt activity specifically through the PH domain. Some of these compounds demonstrated broad cytotoxicity to a wide variety of tumor cells. These novel Akt-inhibiting compositions target the PH domain and help in the prevention and treatment of cancer. Since it has been shown that reducing the activity of the PI3K-Akt pathway sensitizes malignant cells to chemotherapy or radiotherapy, these novel Akt inhibitors have potential either as single anti-cancer agents or in combination with conventional cancer therapies.

One of the candidate compounds inhibited Colony Stimulating Factor-1 Receptor (CSF1R) from binding to ATP but had no activity for other kinases. CSF1R has been implicated in development of cancers like chronic myelomonocytic leukemia, but also in Alzheimer's disease so this specific compound may have use in treating other diseases in addition to cancer. CRADA Opportunity: The Center for Cancer Research, Medical Oncology Branch and Affiliates, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Patient-derived Gastrointestinal Stromal and Paraganglioma Tumor Samples Harboring Novel Stem Cell Factor FOXD3 Variants

Mon, 01 Mar 2010 19:00:00 GMT

The cancer market is forecast to reach $40 billion dollars by the year 2012. There is still a significant need to develop new therapies for treating sarcomas and malignant neoplasms.

Researchers at the National Institute of Child Health and Human Development (NICHD), NIH, have made available samples of patient-derived gastrointestinal tumors (GIST) and paraganglioma tumors that harbor genetic mutations that have an effect on early stage embrogenesis which plays a role in the fate of stem cells. GISTs are one of the most common sarcomas of the gastrointestinal tract with an estimated 5,000-10,000 new cases in the U.S. reported each year. GISTs affect mainly pediatric and young adult patients, and respond poorly to current therapies. Paragangliomas are rare neuroendocrine neoplasms that develop primarily in the abdomen.

The tumor samples made available herein contain deletions in the FOXD3 gene and display down-regulated FOXD3 protein expression. While the majority of GISTs result from activating mutations in the oncogene receptor tyrosine kinases c-KIT and PDGFRA, these tumor samples do not harbor mutations in c-KIT or PDGFRA ("non-KIT/ PDGFRA-GISTs") and respond poorly to receptor tyrosine kinase inhibitors. CRADA Opportunity: The National Institute of Child Health and Human Development Endocrinology & Genetics Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Joseph Conrad, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information.

Compounds that Interfere with the Androgen Receptor Complex: Use in Treating Prostate Cancer or Enlargements, Diabetes, and as Contraceptives

Tue, 02 Mar 2010 00:00:00 GMT

Investigators at the National Institutes of Health (NIH) have discovered compounds that have potential as novel anti-androgen therapeutics. The immunophilin protein FKBP52 is part of a protein complex that helps fold the androgen receptor (AR) protein, a target for treating prostate cancer, and enhances its activity. Disruption of the FKPB52-AR interaction greatly reduces the activity of the AR. With the goal of finding potential therapeutic compounds that inhibit the FKBP52-mediated activation of AR, several small molecules were tested and found to be antagonists of FKBP52 and to inhibit AR activity in prostate cells. These compounds can serve as therapeutics for the treatment of prostate cancer and benign prostate enlargement. Moreover, FKBP52 is also implicated in the regulation of other hormone receptors so these compounds could be used to treat other hormone-dependent diseases such as diabetes or even used as contraceptives.

One of the standard treatments for prostate cancer makes use of anti-androgens, like bicalutamide, which compete for binding with the natural male hormones to AR and inhibit their proliferative activity. The problem with available anti-androgen drugs is that prostate tumors eventually become drug resistant resulting in so-called androgen-resistant prostate cancer. One cause of this is an increase in the levels of AR produced by the prostate cancer cells. A solution to this problem may lie in disrupting the protein folding of AR by interfering with its interaction with FKBP52 using these compounds. CRADA Opportunity: The Center for Cancer Research, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antagonists of FKBP52-dependent remodeling of the androgen receptor. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Detection of Autoantibodies for the Diagnosis of Sjogren's Syndrome

Mon, 25 Jan 2010 05:00:00 GMT

This invention provides a method for diagnosing Sjogren's syndrome in a subject. In tests utilizing blood from human volunteers, this method demonstrated dramatically higher accuracy (76%) in positively diagnosing Sjogren's syndrome than a standard, currently available immunoassay (46%).

Briefly, this invention employs a panel of mammalian-derived proteins and protein fragments that are often antigentic in individuals with Sjogren's syndrome in concert with a luciferase immunoprecipitation system. In contrast, most currently available immunoassays for diagnosis of rheumatological diseases include either antigens from recombinant bacterial expression systems or single antigens from bovine sources. These immunoassays are likely to fail to present the sufficient variety of specific human epitopes that are necessary for high accuracy diagnoses of Sjogren's syndrome. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Laboratory of Sensory Biology, Neurobiology and Pain Therapeutics Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

Novel Analogues of the Natural Product Schweinfurthin with Specificity for Tumors and Other Disease Manifestations Associated with Neurofibromatosis Type 1

Mon, 25 Jan 2010 10:00:00 GMT

The global anti-cancer market is forecast to reach $40 billion by 2012. There remains a significant unmet need for therapies to treat neurofibromatosis type 1 ("NF1"), a common genetic disease that afflicts 1 in 3500 people, and malignant tumors carrying NF1 mutations, including tumors of the central and peripheral nervous systems.

Researchers at the National Cancer Institute ("NCI")-Frederick investigating genetic influences on cancer susceptibility of the nervous system have synthesized novel analogues of Schweinfurthin, a natural compound first isolated from the tropical African plant Macaranga schweinfurthii, to which glioma and leukemia cell lines show significant sensitivity. The Schweinfurthin analogues also have inhibitory activity against mouse and human NF1 cancer cell lines. The analogues have a novel mode of action that appears to involve regulation of cytoskeletal reorganization.

These inhibitors are likely to be accepted in the marketplace because their potent, selective activity and unique specificity in mode of action gives them a distinct advantage over the mechanisms of other existing therapies. CRADA Opportunity: The Genetic Modifiers of Tumorigenesis Section at the National Cancer Institute-Frederick is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Schweinfurthins for the treatment of Neurofibromatosis type 1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Mouse Macula Densa Cell Line

Mon, 25 Jan 2010 15:00:00 GMT

This technology provides a clonally derived macula densa cell line (MMDD1 cells) that closely mimics the known molecular expression pattern of native macula densa (MD) cells. MMDD1 cells are developed from SV-40 transgenic mice using fluorescence-activated cell sorting of renal tubular cells labeled with segment-specific fluorescent lectins. The MMDD1 cells of this technology express COX-2, bNOS, NKCC2, and ROMK, but not Tamm-Horsfall protein, and show rapid ⁸⁶Rb⁺ uptake that is inhibited by a reduction in NaCl concentration and by bumetanide or furosemide. These MMDD1 cells provide a useful in vitro model for the study of Macula Densa function. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases Kidney Disease Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the clonally derived macula densa cell line (MMDD1 cells). Please contact Cindy Fuchs at 301-451-3636 for more information.

Method for the Treatment of HIV/AIDS Infection Using Acyclovir in Identified Subjects

Mon, 25 Jan 2010 20:00:00 GMT

The invention provides the novel method to treat HIV infections with acyclovir which can be converting to acyclovir triphosphate inside infected cells. Acyclovir or acyclovir-related drugs were previously approved for control of herpesvirus replication with 20 years of records of safe application. The subject invention demonstrates that acyclovir triphosphate can inhibit HIV-1 reverse transcriptase as a potent suppressor of HIV-1 replication in human lymphoid tissues. In addition, the subject invention may be attractive to potential licensees, as there is little to not FDA hurdle to overcome in the development of the new formulations to use in this manner. Thus, the low cost and proven safety of acyclovir may lead to a new medicine for treating HIV-1 infections and a prophylactic agent for preventing HIV infections. CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Program in Physical Biology, Section on Intracellular Interactions, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Joseph Conrad, Ph.D., J.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information.

Signal-to-Noise Enhancement in Imaging Applications Using a Time-Series of Images

Tue, 26 Jan 2010 01:00:00 GMT

The invention offered for licensing relates to the field of imaging and specifically to the field of medical imaging. The apparatus and method of the invention provide for noise reduction in imaging applications that use a time-series of images. In one embodiment of the invention, a time-series of images is acquired using a same imaging protocol of the same subject area, but the images are spaced in time by one or more time intervals (e.g. 1, 2, 3 …seconds apart). A sub-region is projected across all of the images to perform a localized analysis (corresponding X-Y pixels or X-Y-Z voxels are analyzed across all images) that identifies temporal components within each sub-region. Subsequently, within the sub-regions, only those temporal components are selected whose amplitude is above a predetermined amplitude threshold. The images are then reconstructed using the sub-regions with reduced components. A maximal-intensity-projection (MIP) is applied in the temporal domain (tMIP) in order to obtain a single image with reduced noise (this can be done either at the sub-region level or at the reconstructed image level). The technology can be applied to a broad spectrum of medical imaging technologies such as MRI, X-Ray, CT and others. CRADA Opportunity: The National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to implement the technology described above on specific commercial platforms. Please contact Denise Crooks, Ph.D. at 301-435-0103 or via e-mail at crooksd@nhlbi.nih.gov for more information.

Diagnostic Tool for Diagnosing Benign Versus Malignant Thyroid Lesions

Fri, 22 Jan 2010 06:00:00 GMT

This technology describes a 72 gene model that has been developed for diagnosing less common forms of thyroid cancer like follicular carcinoma and others. The technology detects thyroid cancer using fine needle aspiration (FNA) biopsy and the analysis of differentially expressed thyroid (DET) genes and their encoded proteins. These results provide a molecular classification system for thyroid tumors and this in turn provides a more accurate diagnostic tool for the clinician managing patients with suspicious thyroid lesions. It is related to earlier technology out of the laboratory of Dr. Libutti, US Application No. 11/547,995 entitled "Diagnostic Tool for Diagnosing Benign vs. Malignant Thyroid Lesions" (HHS Reference No. E-124-2004). This latter invention was drawn to a 6 and 10 gene model that distinguishes benign vs. malignant papillary thyroid lesions. CRADA Opportunity: The Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Diagnostic Tool for Diagnosing Benign Versus Malignant Thyroid Lesions. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Mutations of the ERBB4 Gene in Melanoma

Fri, 22 Jan 2010 11:00:00 GMT

Cutaneous malignant melanoma is the most common fatal skin cancer, and the incidence of this disease increases each year. The average survival time for patients diagnosed with malignant melanoma is less than ten months. Consequently, it is important to identify and understand genetic alterations leading to malignant melanoma so that new treatments strategies can be developed.

Protein tyrosine kinases (PTKs) have been associated with a wide variety of cancers, including melanoma. Using high-throughput gene sequencing, the NIH inventors have analyzed PTKs in melanoma and have identified several novel somatic alterations, including alterations in ERBB4. This invention provides methods of identifying specific inhibitors to ERBB4 that could be used to treat patients with ERBB4 mutations. Given the recent success of small molecule protein kinase inhibitors and specifically inhibitors to EGFR, this invention could be used further the development of specific inhibitors to ERBB4 and improve existing melanoma treatments for patients with these mutations. CRADA Opportunity: The Cancer Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate and/or commercialize an ERBB4-based diagnostic, prognostic and/or theranostic test as well as identify and/or evaluate ERBB4 inhibitor compounds for testing as possible candidate malignant melanoma therapeutic drugs. Please contact Claire Driscoll at cdriscol@mail.nih.gov or Dr. Yardena Samuels at samuelsy@mail.nih.gov for more information.

Preventing Oral Mucositis with Hybrid Adenoretroviral Vectors

Fri, 22 Jan 2010 16:00:00 GMT

Researchers at the National Institutes of Health have recently developed a novel method utilizing adenoretroviral vectors to safely and swiftly prevent oral mucositis induced by radiotherapy. This clever new method developed by National Institute of Dental and Craniofacial Research (NIDCR) researchers combines the advantages of adenoviral and retroviral vectors to efficiently shuttle into salivary glands a non-integrating vector that can produce a therapeutic protein for intermediate to long-term treatment. This approach is anticipated to result in fewer side-effects than current therapies.

The market for the treatment of mucositis, the painful inflammation and ulceration of the mucous membranes lining the digestive tract, is estimated to be in excess of $5 billion world-wide. Up to 80% of all patients receiving radiotherapy and approximately 40% of all chemotherapy patients develop oral mucositis, and almost all patients receiving radiotherapy for head and neck cancer and those undergoing stem cell transplantation develop mucositis. CRADA Opportunity: The National Institute of Dental and Craniofacial Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

Non-Contact Total Emission Detection Methods for Multiphoton Microscopy: Improved Image Fidelity and Biological Sample Analysis

Mon, 28 Dec 2009 21:00:00 GMT

The technology offered for licensing and for further development is in the field of multiphoton microscopy (MPM). More specifically, the invention describes and claims optical designs that can enhance and extend the capabilities of MPM in spectral imaging of biological samples. The unique design of the light collection and the detection optics maximizes the collection of emitted light, thus increasing the signal and hence the signal-to-noise ratio (SNR). Improvement in image fidelity will result in improved analysis of biological samples and thus will favorably impact medical research and possibly clinical diagnosis. The present technology is a further improvement on the TED (Total Emission Detection) technology, first disclosed by Dr. Robert Balaban et al. at the NIH in 2006 and claimed in US patent application 11/979,600, now allowed (Patent Publication US-2008-0063345 A1, March 13, 2008). The earlier NIH TED technology proposed an optical design based on enveloping the entirety of a small sample in a parabolic mirror/condenser combination so light emanated by a sample in all directions is redirected to the detector. The present technology further expands the capabilities of TED as its unique design employing parabolic, toric and conic mirrors ensures maximum light collection from large samples in cases where there is only access to one side of the tissues (e.g., in vivo or ex vivo). This is accomplished by the redirection of all attainable light (i.e., light escaping the tissue or a whole animal in the epi and sideway directions) to the detector. CRADA Opportunity: The NHLBI Laboratory of Molecular Biophysics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize an enhanced method of multiphoton microscopy that is suitable for the spectral imaging of biological samples. Please contact Brian W. Bailey, Ph.D. at bbailey@mail.nih.gov for more information.

Fourier X-ray Scattering and Phase-Contrast Imaging: Enhanced Contrast and Sensitivity of X-ray Images

Tue, 29 Dec 2009 02:00:00 GMT

The invention offered for licensing is broadly applicable to medical diagnostic imaging, biological imaging, industrial non-destructive testing, security screening, and other routine x-ray inspections. The invention provides a method and apparatus that can significantly improve and enhance the contrast and sensitivity of x-ray images. More specifically, the method described in the invention provides a technique to obtain in a single shot x-ray diffraction, differential phase-contrast, as well as the conventional absorption images. X-ray diffraction reveals information about microscopic structures in the imaged object from nanometer to micrometer scales which enables detection of specific materials and disease pathologies that are invisible in conventional x-ray images. The main advantage of the invention over prior art is the single-shot capability without the need to scan an analyzer crystal or grating, and without the need for any hardware beyond standard radiography equipment. It also offers flexibility in hardware configuration to target specific materials by their diffraction signature. For this reason the invention is highly adaptable and well suited for day-to-day applications of x-ray radiography and computed tomography.

In one of the embodiments of the invention for example, a scattering imaging method uses a transmission grid to modulate the intensity of a beam of an x-ray radiation source. A detector captures a raw image from the modulated intensity pattern. A diffraction image can be automatically generated from the detected modulated intensity pattern.

In yet another embodiment, both a diffraction image and a differential phase-contrast image are obtained in a single exposure. Advantageously, commercially available x-ray grids and radiography machines can be used for this method, and exact positioning of the grid is unnecessary, as the method works for any non-zero distance between the grid and the detector. Thus, the speed and ease of implementation makes it suitable for both planar radiography and 3D computed tomography. In addition to its medical diagnostics significance, the invention can be utilized in other, non-medical applications such as non-destructive inspections and security screening. CRADA Opportunity: The National Heart, Lung, and Blood Institute, Laboratory of Cardiac Energetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize single-shot x-ray diffraction and phase-contrast imaging. Please contact Denise Crooks at 301-402-5579 or crooksd@nhlbi.nih.gov for more information.

Method of Preventing and Treating Metastatic Disease

Mon, 28 Dec 2009 07:00:00 GMT

Cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy appears to arise from tumor cells that disseminated early in the course of disease but did not develop into clinically apparent lesions. These long-term surviving, disseminated tumor cells maintain a state of dormancy, but may be triggered to proliferate through largely unknown factors. Inventors at the National Institutes of Health have discovered agents that prevent or treat recurrent metastatic cancer by inhibiting type I collagen production and downstream signaling through beta 1 integrin activation. Blocking activation of beta-1 integrin signaling using pharmacological approaches or using RNA interference was found to prevent reorganization of the cytoskeleton that is associated with proliferation of the dormant tumor cells. The technology provides compositions and methods for modulating the switch from tumor cell dormancy to proliferation clinical metastatic disease in a patient by administering beta-1 integrin signaling inhibitors. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cancer Biology and Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Optimizing Chemotherapeutic Performance: Three Newly-Identified Classes of Tyrosyl-DNA Phosphodiesterase (Tdp1) Inhibitors

Mon, 28 Dec 2009 12:00:00 GMT

During replication, DNA is structurally modified and cleaved by a host of enzymes, including topoisomerases. Some chemotherapeutic agents generate their anti-cancer activity by inducing DNA damage in rapidly replicating tumor cells, resulting in cell death. Topoisomerase I (top1) inhibitors, such as camptothecins, are common chemotherapeutics that prevent the religation of DNA after cleavage during replication.

Tyrosyl-DNA phosphodiesterase (Tdp1) counteracts the action of these chemotherapeutic agents and can reduce their effectiveness in eliminating tumor cells. Tdp1 is an enzyme that repairs DNA lesions and chemotherapeutic-mediated DNA damage, such as the DNA breaks induced by top1 inhibitors. Therefore, Tdp1 is a rational anticancer target whose inhibition should enhance the activity of common cancer chemotherapeutics by permitting greater DNA damage in tumor cells.

Scientists at the National Institutes of Health (NIH) have discovered three classes of compounds that specifically inhibit Tdp1, including cephalosporin derivatives like beta-lactam antibiotics, ellagic acid derivatives such as polyphenol antioxidants, and verteporfin derivatives including protoporphyrins. The compounds were identified as specific Tdp1 inhibitors via a high-throughput screening assay (AlphaScreen^TM) of the NIH Roadmap Molecular Libraries Small Molecule Repository (MLSMR). One current goal of the scientists is to identify the compounds with the greatest Tdp1specificity and highest inhibitory activity against cancer cell proliferation. Some of the compounds identified are widely used to treat a variety of other diseases, including bacterial infections (beta-lactam antibiotics) and neurodegenerative and cardiovascular disorders (polyphenol antioxidants).

Now, through studies at the NIH, these compounds identified as Tdp1 inhibitors could be utilized to potentiate the pharmacological action of top1 inhibitors in the treatment of cancer with combination drug therapies. Top1 inhibitor/Tdp1 inhibitor combination chemotherapies are anticipated to be more selective against tumor tissues than top1 inhibitors alone. In addition, since Tdp1 is involved in repairing DNA damage caused by oxygen radicals and tumors are known to contain excess free radicals, Tdp1 inhibitors may also prove useful as anticancer agents independent of their use in conjunction with top1 inhibitors. CRADA Opportunity: The National Cancer Institute, Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize topic of invention or related laboratory interests. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Device for Sterile Removal of a Biological Sample from a Cryopreserved Bag

Mon, 28 Dec 2009 17:00:00 GMT

Cryopreservation through freezing in liquid nitrogen allows the storage of biological materials for extended periods while maintaining their activity and viability. It is commonly used in the clinic to store blood cells, semen, and umbilical cord blood (UCB) for future use. These materials are typically only obtainable in limited quantities and may be of great therapeutic value, as is the case of hematopoietic stem cells from UCB which can be used to treat and cure a number of different life-threatening illnesses. It is common practice to cryopreserve viably in bags a variety of different cells obtained from the blood . Currently, even if only a small portion of the cryopreserved sample is needed the whole bag must be thawed, wasting much of the sample since it cannot be effectively refrozen. There is a need for a method of retrieving a small sample from a frozen sample of cells in a bag while preserving the cryopreserved state and integrity of the rest of the cellular material.

Researchers at the National Heart, Lung, and Blood Institute in collaboration with the American Fluoroseal Corporation (AFC) have invented an apparatus that separates a small portion of a cryopreserved biological material stored in a collection bag while maintaining the cryopreserved integrity, sterility, and viability of the original cryopreserved material. This device could be used to retrieve small aliquots samples of various cryopreserved cellular products and biological materials such as UCB, blood mononuclear cells, stem cells, semen, and plasma while maintaining the viability and sterility of both the retrieved sample and the original cryopreserved material. CRADA Opportunity: The National Heart, Lung, and Blood Institute, Hematology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Device for Sterile Removal of a Biological Sample from a Cryopreserved Bag. Please contact Cecilia Pazman, Ph.D., 301-402-5579; pazmance@mail.nih.gov for more information.

Synergy of ABT-737 with an Immunotoxin to Kill Cancer Cells

Mon, 28 Dec 2009 22:00:00 GMT

Programmed cell death (i.e., apoptosis) represents an attractive approach for treating cancer. However, anti-apoptotic proteins that are frequently active in cancer cells can allow the cells to survive induction of apoptosis. While inhibiting anti-apoptotic proteins has shown promise in combination with apoptosis-inducing treatments, current inhibitors only show incomplete effectiveness in promoting the induction of apoptosis.

ABT-737 is one such inhibitor; it can only inhibit the function of three of the four major anti-apoptosis proteins. The fourth member, known as a MCL1, is a short-lived protein that can still prevent apoptosis in the presence of ABT-737. Importantly, because MCL1 is a short-lived protein, it requires protein synthesis to maintain levels that are sufficient to continue blocking apoptosis.

This technology uses a combination approach in the treatment of cancer. The inventors considered that combining ABT-737 with a protein synthesis inhibitor might completely inhibit anti-apoptotic proteins, leading to efficient induction of apoptosis. Specifically, NIH inventors found that combining ABT-737 and immunotoxins did result in enhanced killing of cancer cells. Because immunotoxins function by inhibiting protein synthesis, the two agents in combination are able to inhibit all of the anti-apoptotic proteins simultaneously. Furthermore, immunotoxins can be specifically targeted to cancers cells, thereby increasing their effectiveness over a non-specific protein synthesis inhibitor. The results suggest that the combination could represent an effective approach to enhancing the induction of apoptosis as an anti-cancer therapy. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Vaccines Against Malarial Diseases

Thu, 24 Dec 2009 03:00:00 GMT

The invention offered for licensing is in the field of use of vaccines for malaria. The invention provides gene sequences encoding an erythrocyte binding protein of a malaria pathogen for the expression of the erythrocyte binding protein. The codon composition of the synthetic gene sequences approximates the mammalian codon composition. The synthetic gene sequences are useful for incorporation into DNA vaccine vectors, for the incorporation into various expression vectors for production of malaria proteins, or both. The synthetic genes may be modified to avoid post-translational modification of the encoded protein in other hosts. Administration of the synthetic gene sequences, or the encoded protein, as an immunization agent is useful for induction of immunity against malaria, treatment of malaria, or both. The approach presented in this invention, i.e. vaccine that may block the binding of the malaria parasite and subsequent erythrocyte invasion, may work independently or in combination with other vaccines which are based on different mechanisms. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the erythrocyte binding protein as a malaria vaccine. Please contact Dana Hsu at 301-496-2644 for more information.

Device and Method for Direct Measurement of Isotopes of Expired Gases: Application in Research of Metabolism and Metabolic Disorders, and in Medical Screening and Diagnostics

Wed, 23 Dec 2009 08:00:00 GMT

The technology offered for licensing and for further development concerns a novel device for intervallic collection of expired gas from subjects and subsequent measurement of the isotopic content of such expired gases. The device is specifically designed for medical research and clinical applications, and in particular in the area of metabolic disorders. The device may facilitate the development and testing of new therapies for such disorders and may be used for medical screening and diagnostics of metabolic diseases. The unique design of the device includes a constant volume respiratory chamber equipped with a series of valves and stopcocks to allow precise and repetitive removal of expired gases, and addition of air or other gas to maintain the chamber at a constant volume. Also included is a vacuum tube adapter linked to a port on a three-way stopcock to allow facile transfer of the chamber gases to vacuum tubes for subsequent chemical analyses. The device also includes gas sensors operably linked to detectors and inserted to the chamber through airtight ports; this allows the operator to independently and directly measure the carbon dioxide production rate and oxygen consumption of the test subject while the expired gases are removed for study.

The experimental subject (e.g. mammal) is first contacted with a substrate (e.g. amino acid, fatty acid, organic acid) containing an isotope (e.g. ¹³C) and placed in the chamber. The unique design allows easy gas removal and addition while maintaining a constant chamber volume. Precisely measured air samples are collected from the chamber by the syringe and subsequently transferred to a self-sealing vacuum tube which is then removed for analysis. Subsequent sampling is accomplished in the exact same manner, after an equivalent volume of ambient air, or other gas such as pure oxygen, is reinjected in the chamber to maintain pressure and volume. Air samples from the chamber are collected periodically and the content of the isotope (¹³C) accumulated in the chamber gas due to metabolism and the formation of ¹³CO₂ is measured (e.g. via Isotope Ratio Mass Spectroscopy (IRMS)) from the collected samples. The rate of the metabolite's development (i.e. ¹³CO₂) can thus be determined and can thus provide information on the metabolic status of the subject, such as the rate and extent of oxidation of the administered isotope. Furthermore, results of such analysis can provide fundamental information on the ability of the subject to metabolize a compound, quantitate the effectiveness of an experimental therapy (i.e. enzyme replacement, gene therapy, hormone administration, etc.) and thus facilitate progress in the development of interventional therapies. CRADA Opportunity: The Organic Acid Research Section, Genetic and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology or related laboratory interests. Please contact Claire T. Driscoll at cdriscol@mail.nih.gov for more information.

Small-Molecule Inhibitors of Angiogenesis

Wed, 02 Dec 2009 13:00:00 GMT

Angiogenesis, the growth of new blood vessels from existing vessels, is a normal and vital process in growth and development. Deregulation of angiogenesis plays a role in many human diseases, including cancer, age-related macular degeneration, diabetic retinopathy, and endometriosis.

NCI investigators have used a cell-based high-throughput screening method to identify a set of anti-angiogenic small molecules. These compounds are highly active, inhibiting both endothelial cell growth and tube formation, and are not cytotoxic. Structure-activity relationship analysis has revealed that these compounds are unrelated to known anti-angiogenic compounds, and hence may operate through a novel mechanism of action. Thus, these compounds would be promising candidates for the development of new anti-angiogenesis therapeutics. CRADA Opportunity: The National Cancer Institute Angiogenesis Core Facility is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a new set of non-cytotoxic antiangiogenic small molecules. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Antibody Composition and Methods for the Prevention and Treatment of Lupus Nephritis

Mon, 30 Nov 2009 18:00:00 GMT

This technology identifies an antibody that induces a protective effect in vivo in a mouse model of lupus nephritis. Lupus is a chronic autoimmune disease that can damage various parts of the body, especially the kidneys. The lupus nephritis-model mice that were treated with this antibody experienced a dramatic increase in survival, demonstrated a reduced immune complex formation deposition in the kidneys, and displayed low levels of proteinuria as compared with untreated mice. The antibody is an autospecific anti-dsDNA IgM.

In addition, this invention may be used as a component of a predictive diagnostic kit. As lupus-related kidney disease may be asymptomatic, significant kidney damage may occur before lupus is diagnosed (lupus.org). The inventors are currently investigating whether the ratio of protective antibodies to nonprotective or pathogenic antibodies in lupus nephritis models is predictive of disease. Currently available diagnostic methods (proteinuria, creatine clearance, or kidney biopsy) are not predictive and test only for existing kidney impairment or damage. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology or related laboratory research interests. Please contact Dr. Elizabeth Denholm at denholme@niehs.nih.gov or 919-541-0981 for more information.

RORgamma (RORC) Deficient Mice Which Are Useful for the Study of Lymph Node Organogenesis and Immune Responses

Mon, 23 Nov 2009 23:00:00 GMT

The retinoid-related orphan receptor gamma (RORgamma) is a member of the nuclear receptor superfamily. NIH investigators used homologous recombination in embryonic stem cells to generate mice in which the RORgamma gene was disrupted. RORgamma deficient mice lack peripheral and mesenteric lymph nodes and Peyer's patches indicating that ROR expression is indispensable for lymph node organogenesis. In addition, RORgamma is required for the generation of Th17 cells which play a critical role in autoimmune disease.

The RORgamma deficient mice are useful to identify the physiological functions of the RORgamma. RORgamma deficient mice also provide an excellent tool to study the role of RORgamma in immune responses and autoimmune disease, the study of the role of Th17 and interleukin 17 in these processes, and the analysis. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the ROR gamma mice or related laboratory research interests. Please contact Dr. Elizabeth Denholm at denholme@niehs.nih.gov or 919-541-0981 for more information.

Clk and Dyrk1A Inhibitors as General Splicing Modulators and for the Potential Treatment of Down's Syndrome and Alzheimer's Disease

Tue, 24 Nov 2009 04:00:00 GMT

NIH investigators have discovered a series of potent, selective small molecule inhibitors of cdc2-like kinases (Clk) and dual-specificity tyrosine-regulated kinase 1A (Dyrk1A) with potential as modulators of gene splicing and within the treatment of Down's syndrome and Alzheimer's disease. Clk kinases are known to phosphorylate the prominent family of serine- and arginine-rich (SR) splicing proteins. Members of the Clk family have been implicated in the regulation of alternative splicing of PKCbetaII, TF, Tau and beta-globin pre-mRNA. Dyrk1A is a kinase that has been implicated in numerous aspects of neurological development and maintenance. The gene that encodes Dyrk1A is found on the Down's Syndrome-critical region on chromosome 21 and the over-expression of Dyrk1A is considered to be a primary contributor to the Down's syndrome phenotype. For instance, transgenic mice overexpressing Dyrk1A exhibit cognitive deficits, and blocking Dyrk1A in these transgenic animals has been shown to mitigate Down's-related deficits. Hyper-phosphorylation of Tau by Dyrk1A has also been directly implicated in the pathology and progression of Down's syndrome-associated Alzheimer's disease. Alzheimer's disease in general is also associated with pathological deposition of hyper-phosphorylated Tau. Thus, these molecules have the potential to treat both Down's syndrome and Alzheimer's disease. CRADA Opportunity: The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/247,632. Please contact Dr. Craig J. Thomas via e-mail (craigt@nhgri.nih.gov) for more information.

Potent and Selective Inhibitors of Human Lipoxygenase for Prostate Cancer Therapy

Tue, 17 Nov 2009 09:00:00 GMT

With more than $2 billion in revenues in the US in 2007, the market for diagnostic and therapeutic products for prostate cancer is substantial. More than 2,000,000 American men currently live with prostate cancer and more than 200,000 new cases are diagnosed each year.

Researchers led by Dr. David Maloney at the National Human Genome Research Institute (NHGRI) have discovered several novel compounds that selectively and potently inhibit lipoxygenase (LOX), an enzyme that metabolizes polyunsaturated fatty acids which has been implicated in the pathogenesis of prostate cancers. These novel compounds are small molecules, and as such have an advantage over antibody-based technologies in this market. As prostate cancer is the most commonly diagnosed malignancy among men in the USA and Europe, the significant need for new therapies suggests that these novel LOX inhibitor compounds have a strong potential of reaching the marketplace. CRADA Opportunity: The NIH Chemical Genomics Center, NHGRI, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Claire Driscoll at cdriscol@mail.nih.gov or 301-594-2235 for more information.

Optimized Expression of IL-12 Cytokine Family

Tue, 17 Nov 2009 14:00:00 GMT

The IL-12 family of cytokines (IL-12, IL-23, and IL-27) has an important role in inflammation and autoimmune diseases. IL-12 is produced by macrophages and dendritic cells in response to certain bacterial and parasitic infections and is a powerful inducer of IFN-gamma production. IL-23 is proposed to stimulate a subset of T cells to produce IL-17, which in turn induce the production of proinflammatory cytokines that lead to a protective response during infection. IL-27 appears to have duel functions as an initiator of TH1-type (cellular immunity) immune responses and as an attenuator of immune/inflammatory responses.

The present inventions provide methods for improved expression of multimeric proteins by engineering different ratios of the subunit expression units in a cell or upon expression from a multi-promoter plasmid having different strength promoters. The inventors have improved the levels and efficiency of expression of the IL-12 family of cytokines, which includes IL-12, IL-23, and IL-27, by adjusting the transcription and translation of the alpha and beta subunits that comprise the heterodimeric proteins. Optimal ratios of expression for the two (2) subunits were determined for IL-12, IL-23, and IL-27. CRADA Opportunity: The Center for Cancer Research, Human Retrovirus Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize delivery of cytokines of the IL-12 family in cancer and other indications. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Immunotoxin Useful for Treatment of AIDS

Wed, 04 Nov 2009 19:00:00 GMT

Human Immunodeficiency Virus (HIV) attacks and destroys T cells, leading to the development of Acquired Immunodeficiency Syndrome (AIDS) in patients. Although significant progress has been made treating patients with AIDS, an effective cure has yet to be identified. For example, highly active antiretroviral therapy (HAART) has shown dramatic reduction of viral replication while allowing recovery of the immune system in HIV patients. However, HAART does not directly kill HIV-infected T cells, allowing the virus to persist in the body and resume replication and infection of T cells after HAART is stopped. This ultimately results in a return to pre-treatment levels of viral replication and the persistence of the disease in patients.

The current technology concerns an invention that can be used to address this limitation of HAART. An immunotoxin has been created that targets a toxin (PE38) to the HIV-specific Envelope glycoprotein (gp120) that is displayed on the surface of T cells that have been infected with the HIV virus. The immunotoxin kills the HIV-infected T cells and other infected cell types that serve as a viral reservoirs during HAART, thereby reducing the ability of the virus to replicate and infect other cells after HAART is stopped. Recent data shows that the immunotoxin blocks the spread of HIV-1 in vitro and does not induce hepatotoxicity in rhesus monkeys, suggesting the procedure could be effective in human patients. By combining the immunotoxin with a treatment regimen such as HAART, it may be possible to significantly improve treatment of HIV infection. CRADA Opportunity: The Center for Cancer Research, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Phantom for Diffusion MRI: A Method of Enhancing Performance and Reliability

Thu, 05 Nov 2009 00:00:00 GMT

The technology offered for licensing is in the field of Diffusion Magnetic Resonance Imaging (Diffusion MRI). Specifically, a novel imaging phantom is described and claimed. Such a phantom is specifically optimized for Diffusion MRI and is expected to enhance the performance and reliability of this now widespread imaging technology.

The phantom provided in this invention comprises a stable aqueous solution with a concentration of at least 30%, by weight, of a mixture of a high molecular-weight polymer or copolymer and a low molecular-weight polymer or copolymer, the aqueous solution having a resulting water diffusivity from about 2x10^-4 mm²/s to about 3x10^-3 mm²/s. Polyvinyl Pyrrolidone (PVP) is the polymer of choice used in this invention. The phantoms of this invention are uniquely stable, non-toxic, and transportable, and have shown to maintain constant water diffusivity after two years. CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development's Section on Tissue Biophysics & Biomimetics (STBB) is seeking statements of capability or interest from outside parties who are interested in entering into a Collaborative Research and Development Agreement (CRADA) to develop and commercialize the Diffusion MRI Phantom described above. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information.

Treating Cancer with Anti-Angiogenic Chimeric Antigen Receptors

Wed, 04 Nov 2009 05:00:00 GMT

Metastasis, the growth and spread of cancer from a localized tumor to other sites in the body, is promoted by the formation of new blood vessels through angiogenesis to "feed" the tumor. There is an urgent need to develop new therapeutic strategies that combine fewer side-effects and more specific anti-tumor activity in order to block cancer metastasis in patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual's innate and adaptive immune system to fight against specific diseases, including the spread of cancer.

Chimeric antigen receptors (CARs) are hybrid proteins consisting of the portion of an antibody that recognizes a tumor-associated antigen (TAA) fused to protein domains that signal to activate the CAR-expressing cell. Human cells that express CARs, most notably T cells, can recognize specific tumor antigens in an MHC-unrestricted manner with high reactivity. CARs are able to mediate an immune response that promotes robust tumor killing in targeted cells.

Scientists at the National Institutes of Health (NIH) have developed CARs with high affinity for the vascular endothelial growth factor receptor 2 (VEGFR2) (also known as kinase domain region (KDR) in humans and fetal liver kinase-1 (Flk-1) in mice) to utilize as an antiangiogenic tumor therapy. VEGFR2 is expressed on non-cancerous vascular endothelia cells, but is overexpressed on tumor endothelial cells in a variety of cancers, especially solid tumors. VEGFR2 overexpression promotes tumor vasculature, growth, and metastasis. The VEGFR2-specific CARs feature the antigen binding domain of the KDR-1121 or DC101 antibody, which recognize portions of the human and mouse VEGFR2, respectively. This antibody component is fused to the transmembrane and intracellular signaling domains of a T cell receptor (TCR). These CARs combine high affinity recognition of VEGFR2 provided by the antibody portion with the target cell killing activity of a cell expressing an activated TCR. Infusion of these VEGFR2-specific CARs into patients could prove to be a powerful new immunotherapeutic tool for blocking angiogenic cancer metastasis by killing VEGFR2+ tumor cells. CRADA Opportunity: The Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Simpler is Better: The Production of Young Cell Cultures from Tumor Infiltrating Lymphocytes (TIL) Yields More Effective Adoptive Cell Transfer (ACT) Immunotherapies

Wed, 04 Nov 2009 10:00:00 GMT

Available for licensing is an improved method of adoptive cell transfer (ACT) immunotherapy that can be utilized to treat a variety of infectious diseases and cancers, most notably melanoma.

At its foundation, ACT involves isolating lymphocytes with high affinity for a particular antigen, expanding those cells in vitro to produce a greater quantity of reactive cells, and infusing the product cells into patients to attack cells expressing the antigen, such as tumor cells, bacterial cells, or viral particles. Previously utilized ACT procedures have been plagued by technical, regulatory, and logistical problems that have prevented consistently successful clinical outcomes. Through years of research, scientists at the National Institutes of Health (NIH) have made great strides in developing ACT into a viable approach to treat cancer patients. Of note, the ACT protocols developed by NIH scientists have successfully treated patients with refractory metastatic melanoma who started with very few effective treatment options. These NIH scientists have found that isolating cells from the tumor infiltrating lymphocytes (TIL) of a patient tumor sample provides a suitable initial lymphocyte culture for further in vitro manipulations. They have also discovered that taking the isolated cells through one cycle of rapid expansion (including exposure to IL-2), rather than multiple cycles, yields lymphocyte cultures with higher affinity and longer persistence in patients. Also, they have found that administering nonmyeloablative lymphodepleting chemotherapy prior to the reinfusion of lymphocytes creates a more favorable environment within patients for the transferred cells to execute target cell killing. These scientists envision that, for an ACT immunotherapy to gain regulatory approval and successfully treat a wide array of patients, it will need to be rapid, reliable, and technically simple. One of the most critical factors to this approach is the generation of effective lymphocyte cultures that will rapidly and repeatedly attack the target cells when infused into patients.

Scientists at the NIH have developed a method of generating CD8+ selected "young" lymphocyte cultures for infusion into cancer patients. Lymphocytes that spend fewer days in vitro between their initial isolation from TIL and their ultimate reinfusion into patients compared to lymphocytes cultured by previous ACT protocols are considered young lymphocyte cultures. Young lymphocytes, typically 19-35 days old when reinfused into patients, exhibit improved proliferation, survival, and enhanced anti-tumor activity within patients to yield greater tumor regression compared to older lymphocytes, typically 44+ days old. Furthermore, the generation of young lymphocyte cultures is more rapid, reliable, and technically easier than previous ACT culturing methods. Young lymphocytes are isolated from TIL, directed against a single isolated tumor cell suspension, enriched for CD8 expression, and rapidly expanded once using autologous feeder cells without testing the culture for antigen specificity.

This approach to ACT offers a potentially significant improvement and a valuable new immunotherapeutic tool for attacking tumors. For diseases, such as metastatic melanoma, where patients may only have weeks or months of life expectancy, this technology, which provides for improved cell cultures prepared in less time, can make a difference between life and death. In addition, this method might be applicable in treating other diseases such as AIDS, immunodeficiency, or other autoimmunity for which immune effector cells can impact the clinical outcome. CRADA Opportunity: The Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cell and gene therapy technologies, and personalized medicines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Viral Inactivation Using Crosslinkers and Detergents

Wed, 04 Nov 2009 15:00:00 GMT

The subject technology is a method of inactivating enveloped viruses by hydrophobic photoactivatable chemical crossing-linking compounds and detergent treatment. The inactivated viruses may be used as vaccines against the diseases caused by those viruses or as reagents in experimental procedures that require inactivated viral particles. The compounds diffuse into the lipid bilayer of biological membranes and upon UV irradiation will bind to proteins and lipids in this domain, thereby inactivating fusion of enveloped viruses with their corresponding target cells. Furthermore, the selective binding of these chemical crosslinking agents to protein domains in the lipid bilayer may preserve the structural integrity and therefore immunogenicity of proteins on the exterior of the inactivated virus. The additional detergent step effectively eliminates the infectivity of any residual viral particles that are not adequately crosslinked. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of hydrophobic crosslinkers for their use in vaccine development. Interested collaborators are also invited to provide statements for proposed in vitro or in vivo studies using various enveloped viruses. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Live-Attenuated Tularemia Vaccine

Thu, 29 Oct 2009 19:00:00 GMT

The invention provides compositions and methods of use for a modified strain of Francisella tularensis, the causative agent of tularemia, a category A biodefense agent (NIAID classification). Currently, no vaccines are available, and the only approved therapeutics for tularemia are antibiotics that are only effective if delivered early in the infection. The subject invention defines and characterizes mutations in Francisella tularensis that result in attenuated bacteria capable of inducing strong protective immune responses. Thus, these stable mutant strains could be used as efficient live vaccines against tularemia. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize live vaccine strains of Francisella tularensis with defined mutations. Please contact Rosemary Walsh at 301-496-2644 for more information.

A Novel Multimeric CD4 Fusion Protein for Treating HIV Infection

Thu, 29 Oct 2009 23:00:00 GMT

This invention could potentially provide an alternative to antiretroviral therapy (ART), especially in cases where productively-infected cells persist with ART. This multimeric CD4 fusion protein acts as a decoy to inhibit human immunodeficiency virus (HIV-1) entry into host cells. More specifically, this multimeric CD4 inhibits the interaction between HIV-1 gp120 and CD4 present on the surface of CD4 T-cells, the major HIV-1 target cell. There is strong evidence that binding between gp120, as part of a virion spike, and CD4 on cell surface is the first step for HIV entry into host cells. This multimeric CD4 provides a number of advantages over inhibitory CD4 molecules previously developed. First, this CD4 multimer is capable of binding at least 10 gp120 simultaneously with high avidity. Second, it does not enhance HIV infection at suboptimal concentrations, a phenomenon observed with previously developed recombinant CD4 molecules. Third, it has been demonstrated that this CD4 fusion protein hyper-crosslinks CD16 on natural killer (NK) cells and as a consequence delivers an exceptionally strong signal to NK cells, promoting potent Antibody-Dependent Cellular Cytotoxicity (ADCC) and lysis of HIV-infected cells. The inventors have shown that this recombinant CD4 multimer efficiently neutralizes primary isolates from different HIV subgroups.

The invention comprises an immunoglobulin construct having up to 12 amino terminal domains of CD4 (D1D2), the epitope responsible for HIV-1 gp120 binding activity. It also comprises domains of a human IgG1 heavy chain, as well as the IgA tailpiece that drives its polymerization. The two amino terminal domains of CD4 are fused to the CH2CH3 domains (which bears the FC receptor recognition epitopes) of a human IgG1 heavy chain. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this invention. Please contact William Ronnenberg at 301-451-3522 or wronnenberg@niaid.nih.gov for more information.

Prediction of Immune Response Outcomes to Keyhole Limpet Hemocyanin (KLH) Treatment

Wed, 28 Oct 2009 03:00:00 GMT

Keyhole limpet hemocyanin (KLH) is a large, heterogeneous glycosylated protein that is being tested as an immunotherapeutic agent to treat bladder cancer. KLH is approved for use in parts of Europe and Asia and is in late stage clinical trials in the U.S. KLH immunotherapy however only produces a clinical response in approximately 40-50% of patients, and currently there is no good method to select the subset of patients that will respond best to this treatment. This invention revealed that levels of certain serum antibodies can be used as biomarkers to predict the magnitude of the antibody response to the glycoprotein KLH. The best correlations are obtained by using a combination of markers. Since the size of the antibody response correlates with the clinical response, the invention provides a method to select the subset of patients that may benefit most from this form of treatment. CRADA Opportunity: The NCI Center for Cancer Research, Laboratory of Medicinal Chemistry, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a set of serum antibody-based biomarkers for personalized cancer immunotherapy using keyhole limpet hemocyanin (KLH). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel Inhibitors of Interleukin-6 for Kaposi Sarcoma Therapy

Tue, 27 Oct 2009 07:00:00 GMT

The cancer therapy market is forecast to reach $40.9 billion by 2012. With immunosuppressant drugs set for phenomenal growth over the next six years, revenues could reach $26.2 billion by 2014. One market for which there is a significant need for new therapies is cancers induced by Kaposi Sarcoma-associated Herpesvirus (KSHV).

Researchers at the National Cancer Institute have identified novel nucleic acid sequences that act through a unique mechanism to inhibit the expression of interleukin-6 that occurs in cancerous cells transformed by KSHV infection and which promotes cancer cell proliferation. The researchers have also identified a key protein involved in the mechanism which could be inhibited using antibodies.

These inhibitors are likely to be accepted in the marketplace because their unique specificity in mechanism of action gives them a distinct advantage over the mechanisms of other existing therapies. CRADA Opportunity: The NCI Center for Cancer Research, HIV and AIDS Malignancy Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

B-cell Surface Reactive Antibodies for the Treatment of B-Cell Chronic Lymphocytic Leukemia

Mon, 12 Oct 2009 11:00:00 GMT

B-cell chronic lymphocytic leukemia (B-CLL) is a cancer characterized by a progressive accumulation of functionally incompetent lymphocytes. Despite high morbidity and mortality, the only available potential cure is allogeneic hematopoietic stem cell transplantation (alloHSCST). However, there is less than a 50% chance of finding a matching bone marrow or blood donor for B-CLL patients. Other clinically tested targeted therapies such as rituximab and alemtuzumab target both malignant and normal B cells, resulting in immunosuppression.

Available for licensing are fully human monoclonal antibodies that were selected from the first human post-alloHSCT antibody library. The library was generated from a time point after transplantation at which antibodies to B-CLL cell surface antigens peaked, thus indicating its therapeutic value. Utilizing phage display, the investigators generated a panel of fully human monoclonal antibodies that strongly bind to the same epitope on a B-CLL cell surface antigen. Weaker binding to normal B cells, but not to other lymphocytes, was observed. These fully human monoclonal antibodies provide readily available treatment that selectively targets malignant B cells. CRADA Opportunity: The Center for Cancer Research, Experimental Transplantation and Immunology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize fully human monoclonal antibodies selected from post-alloHSCT antibody libraries. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Target for the Development of Diagnostics and Therapeutics for Abnormal Hematopoiesis

Mon, 12 Oct 2009 15:00:00 GMT

The zinc finger protein ZFP36L2 has been shown by the inventors to play an essential role in hematopoiesis, a process that is dysregulated in hematological cancers, anemia, and other conditions. Thus, ZFP36L2 has promise for use in a diagnostic test to detect abnormal hematopoiesis, or as a target for the development of therapeutics to treat abnormal hematopoiesis.

Hematopoiesis is the formation of blood cellular components, through the differentiation of hematopoietic stem cells into lineages with a variety of roles, such as carrying oxygen, immune function, and blood clotting. Abnormally high hematopoiesis can be caused by hematological cancers such as leukemia or lymphoma, or by other myeloproliferative disorders. Abnormally low hematopoiesis can be caused by diseases such as anemia, thrombocytopenia, or myelodysplastic syndrome, and is often a secondary symptom of other conditions, such as cancer, infection, or dialysis.

The inventors have discovered that Zinc finger protein 36 like type-2 (ZFP36L2) plays an essential role in hematopoiesis, possibly by affecting the stability of mRNAs involved in this process. ZFP36L2 is a member of the tristetraprolin (TTP) family, which are mRNA-binding proteins involved in mRNA processing and degradation. The invention discloses methods of detecting abnormal hematopoiesis by detecting abnormal ZFP36L2 expression or a mutation in the ZFP36L2 gene, and methods of controlling abnormal hematopoiesis by modulating levels of ZFP36L2 protein. CRADA Opportunity: The NIEHS Laboratory of Signal Transduction, Polypeptide Hormone Action Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Elizabeth M. Denholm, Ph.D., Director, Office of Technology Transfer, NIEHS, at denholme@niehs.nih.gov for more information.

Susceptibility-Matched Multiwell Plates for High-Throughput Screening by Magnetic Resonance Imaging and Nuclear Magnetic Resonance Spectroscopy

Mon, 12 Oct 2009 19:00:00 GMT

Available for licensing and commercial development is a patent estate that covers multi-well assay plates for high-throughput screening by magnetic resonance imaging (MRI) and nuclear magnetic resonance (NMR) spectroscopy. Multi-well plates are used in a wide variety of high-throughput measurements in clinical chemistry and immunology, as well as in drug discovery and other research applications. Magnetic resonance imaging (MRI) of multi-well plates offers the possibility of performing new kinds of high-throughput assays, including the detection of magnetic nanoparticles attached to or within cells. Moreover, MRI-guided localized nuclear magnetic resonance (NMR) spectroscopy could be used to perform detailed chemical analysis of complex mixtures of metabolites not possible by any other common analytical technique. Best of all, conventional MRI techniques exist which would permit all samples in one or more multi-well plate(s) to be analyzed simultaneously. Unfortunately, conventional multi-well plates typically give poor performance for MRI-based assays since they provide inadequate matching of magnetic susceptibility between the plate, the sample and their surroundings. This results in distortion of the magnetic field within the scanner and thus reduces the sensitivity for detecting magnetic particles and the resolution of NMR spectra.

This invention relates to a new multi-well plate design incorporating one-piece polyetherimide plastic construction for improved magnetic susceptibility matching for aqueous samples. This design can easily be extended to non-aqueous samples by the selection of an appropriate, commercially-available plastic resin or resin blend. Further enhancement in susceptibility matching can be accomplished by combining the new plate design with plugs for each well constructed from the same plastic as the plate. These plugs would allow the entire thickness of each sample to be scanned in chemical analyses, improving signal-to-noise ratio and sensitivity. These plugs can optionally be integrated into a single "cap mat" so that the entire assembly can be filled and manipulated by standard robotic laboratory equipment already in wide use in the pharmaceutical industry. Alternatively, spherical wells, accessed by narrow fill holes, may be molded into a solid plate, eliminating the need for individual plugs to seal each well. The new multi-well plate/plug design reduces magnetic field distortions and should dramatically improve spectral resolution and sensitivity for NMR and MRI-based high-throughput screening. CRADA Opportunity: The National Institute on Aging, Magnetic Resonance Imaging & Spectroscopy Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Nicole Darack, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information.

Engineered Biological Pacemakers

Sat, 10 Oct 2009 23:00:00 GMT

A common symptom of many heart diseases is an abnormal heart rhythm or arrhythmia. While effectively improving the lives of many patients, implantable pacemakers have significant limitations such as limited power sources, risk of infections, potential for interference from other devices, and absence of autonomic rate modulation.

The technology consists of biological pacemakers engineered to generate normal heart rhythm. The biological pacemakers include cardiac cells or cardiac-like cells derived from embryonic stem cells or mesenchymal stem cells. The biological pacemakers naturally integrate into the heart. Their generation of rhythmic electric impulses involves coupling factors, such as cAMP-dependent PKA and Ca²⁺-dependent CaMK II, which are regulatory proteins capable of modulating/enhancing interactions (i.e. coupling) of the sarcoplasmic reticulum-based, intracellular Ca²⁺ clock and the surface membrane voltage clock, thereby converting irregularly or rarely spontaneously active cells into pacemakers generating rhythmic excitations. CRADA Opportunity: The National Institute on Aging, Cellular Biophysics Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Vio Conley at 301-496-0477 or conleyv@mail.nih.gov for more information.

Neutralization of Hepatitis C Virus (HCV)

Thu, 08 Oct 2009 03:00:00 GMT

Available for licensing and commercial development are compositions and methods for preventing and/or treating infection caused by hepatitis C virus (HCV). The invention is based on mapping studies conducted by the inventors of two epitopes within HCV E2: epitope I and epitope II. It has been discovered that epitope I is involved in virus neutralization but that epitope II mediates antibody interference, probably an adaptation of the virus to obfuscate the immune system. In an effort to attenuate or disable the interference effect of HCV-E2 epitope II, the present invention is directed to a HCV E2 polypeptide substitution/deletion of native amino acids LFY in epitope II, a HCV E2 polypeptide insertion of amino acids between the native LFY in epitope II, or the use of epitope II as a molecular decoyant or to affinity-purify an immune globulin to deplete interfering antibodies from, and enrich neutralizing antibodies in, the preparation. CRADA Opportunity: The FDA Center for Biologics Evaluation and Research, Laboratory of Plasma Derivatives, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Alice Welch, Ph.D. at 301-827-0359 or Alice.Welch@fda.hhs.gov for more information.

Novel Chemoattractant-Based Toxins to Improve Vaccine Immune Responses for Cancer and Infectious Diseases

Wed, 23 Sep 2009 07:00:00 GMT

Cancer is one of the leading causes of death in United States and it is estimated that there will be more than half a million deaths caused by cancer in 2009. A major drawback of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Immunotherapy has taken a lead among the new therapeutic approaches. Enhancing the innate immune response of an individual has been a key approach for the treatment against different diseases such as cancer and infectious diseases.

This technology involves the generation of novel chemoattractant toxins that deplete the T regulatory cells (Treg) or other immunosuppressive or hyperactivated cells locally. Treg controls activation of immune responses by suppressing the induction of adaptive immune responses, particularly T cell responses. Immunosuppressive cells such as tumor infiltrating macrophages, regulatory T cells, regulatory B cells, or NKT and other cells down regulate antitumor immune responses. The chemoattractant toxins consist of a toxin moiety fused with a chemokine receptor ligand, such as chemokines and various chemoattractants, that enables specific targeting and delivery to the regulatory cells. This technology is advantageous over the more harmful antibodies and chemicals that are currently used for the systemic depletion of regulatory cells. The current technology can be used therapeutically in a variety of ways. They can be used together with vaccines to increase efficacy of the vaccine for the treatment of cancer, and can used to locally deplete Treg, Bregs, or other immuno suppressive cells to induce cytolytic cell responses at the tumor site or to eliminate chronic infectious diseases such as HIV and tuberculosis. CRADA Opportunity: The Immunotherapeutics Unit, National Institute on Aging, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Chemotoxin technology for clinical use or as a laboratory tool for depletion of cells. Please contact Nicole Darack, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information.

Bactericidal Peptides from Avian Leukocyte Ribonuclease A-2

Fri, 18 Sep 2009 11:00:00 GMT

These bactericidal polypeptides offer a novel alternative to conventional antibiotics that are used to treat and prevent bacterial infections. As infection-causing bacteria continue to develop antibiotic resistance to first line antibiotics there will always be a need for new antibiotic alternatives. Additionally, a greater understanding of the specific cytoxic activity of RNase A ribonucleases, their functional domains, and their roles in promoting anti-pathogen host defense may provide insight into new therapeutic agents.

This invention includes a novel RNase A ribonuclease from chicken leukocytes and polypeptides that have bactericidal activities against both gram positive and gram negative bacteria, including such pathogens as Escherichia coli, Salmonella spp., and Staphylococcus. CRADA Opportunity: The NIAID Laboratory of Allergic Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact William Ronnenberg, NIAID Office of Technology Development, at 301-451-3522 or wronnenberg@niaid.nih.gov for more information.

RNA Nanoparticles and Methods of Use

Fri, 18 Sep 2009 15:00:00 GMT

The invention hereby offered for licensing is in the field of nanoparticles and their usefulness in a variety of medical applications. More specifically the invention describes the design and synthesis of various RNA nanoparticles. These polyvalent nanoparticles comprise RNA motifs as building blocks that give the particles their unique characteristics. Moreover, the motifs can be pre-defined and chosen to give the particles desired characteristics (e.g. size and shape) tailored for a variety of applications. The polyvalent particles can utilize multiple unique positions to carry functional groups for cell recognition (e.g. cancer cells), therapy and detection. For therapeutic or detection applications the particles typically encompass at least two functional groups, a therapeutic or imaging agent and a targeting agent that will direct the particles to the targeted tissue.

RNA nanoparticles have the potential to serve as excellent drug or imaging delivery systems due to their designability and versatility. Furthermore, the RNA nanoparticles of the invention are also capable of self-assembly and potentially form nanotubes of various shapes which offer potentially broad uses in medical implants, gene therapy, nanocircuits, scaffolds and medical testing. CRADA Opportunity: The National Cancer Institute's Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize RNA nanostructures. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Osmogels: A New Method for Stabilizing Weak Molecular Complex Interactions

Fri, 18 Sep 2009 19:00:00 GMT

This invention describes a new method for stabilizing molecular complexes in polyacrylamide gels for analysis by the electrophoretic mobility shift assay. By adding specific osmolytes directly to the gel, investigators have found that weakly interacting molecular complexes can be sufficiently stabilized to allow quantitative analysis of the binding. Experiments with nonspecific labile complexes of two restriction endonucleases, EcoRI and BamHI, show that one of these added solutes is particularly effective at inhibiting complex dissociation, does not interfere with normal gel polymerization, and does not significantly slow normal gel migration. The results also demonstrate that sharp bands can be obtained for non-specific complexes of both enzymes on gels prepared with this solute while only smeared and distorted bands are observed on regular gels prepared without the solute. This method can be used for protein-protein, DNA-protein, and RNA-protein complexes, and can also be extended to include other techniques for separating complexes from free components using gel chromatography and capillary electrophoresis.

The potential market for gels that allow researchers to detect and quantify weak molecular complex interactions is significant; ranging from molecular biologists searching for novel regulatory DNA-binding proteins and convenient ways to detect protein-protein, or protein-DNA/RNA complexes to crystallographers needing reliable techniques to search for optimal conditions of complex formation. This technology has the potential to significantly impact biomedical research and development across many fields. CRADA Opportunity: The National Institute of Child Health and Human Development, Program in Physical Biology, Laboratory of Physical and Structural Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize osmogels for analysis of weak complexes by the electrophoretic mobility shift assay with potential extension of the technique to other separation methods. Please contact Joseph Conrad III, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information.

Mouse Embryonic Stem Cell-based Functional Assay to Evaluate Mutations in BRCA2

Thu, 17 Sep 2009 23:00:00 GMT

Mutations in breast cancer susceptibility genes BRCA1 and BRCA2 have up to an 80% life time risk in developing breast cancer. There are no “mutation hot spots” and to date, more than 1,500 different mutations have been identified in BRCA2. The absence of tumor cell lines expressing various mutant BRCA2 alleles has hindered evaluations to determine the functional differences between different mutations.

A simple, versatile and reliable mouse embryonic stem cell and bacterial artificial chromosome based assay to generate cell lines expressing mutant human BRCA2 has been developed and it has been used to classify 17 sequence variants. Available for licensing are a wild-type and eleven mutant BRCA2 cell lines developed from this assay that have either truncations or point mutations. These cell lines may be used to evaluate the effect of DNA damaging agents, genotoxins and chemotherapeutic efficacy. CRADA Opportunity: The Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize mouse embryonic stem cell lines suitable for functional analysis of BRCA2 variants. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Establishment of Two Cell Lines that Stably Express Luciferase for In Vivo Tracking

Fri, 18 Sep 2009 03:00:00 GMT

Available for licensing are two renal carcinoma cell lines, 786-O(luc) and 786-O/VHL/(luc) which both stably express luciferase. 786-O(luc) lacks von Hippel-Landau (VHL) protein expression and it has constitutively high expression of hypoxia-inducible transcription factor-2alpha (HIF-2alpha). The second stably expresses VHL, a tumor suppressor, and has minimal HIF-2apha expression. These cell lines can be tracked in vivo and can be used to study VHL-dependent and HIF-2apha dependent events such as tumorigenesis. VHL mutations lead to the clinical manifestations of von Hippel-Lindau disease, a rare autosomal dominant syndrome characterized by abnormal growth of blood vessels in multiple organs, including the brain and kidneys. CRADA Opportunity: The National Cancer Institute, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to develop further uses for these two cell lines that stably express luciferase for in vivo tracking. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Identification of Recent HIV-1 Infection by Genotypic Analysis for Treatment Strategy

Thu, 10 Sep 2009 07:00:00 GMT

This invention describes a bioinformatics algorithm capable of distinguishing between recently infected and chronically infected HIV-1 patients based on the genetic diversity of HIV pro-pol sequences. Directly after infection with HIV-1, genetic diversity is extremely low. Previously, single genome sequencing was used to demonstrate that HIV-1 genetic diversity accumulates after infection in a linear and predictable fashion during the first 8-10 months of infection (Kearney et al., 2009). Using single genome sequencing, it is possible to determine whether a person had been infected with HIV-1 in the recent past. Single genome sequencing is, however, a research technique that is relatively labor intensive and somewhat expensive, making it less feasible for routine use. The invention improves on this analysis in both ease and cost, and is capable of estimating genetic diversity using a population-based sequence that is obtained by routine, commercially available genotyping through the determination of genotype sequence ambiguity, which resulted in both sensitive and specific identification of acute versus chronic infection. The algorithm is also capable of simultaneously determining drug resistance profiles, further representing significant improvement over current antibody-based methods. Since recent data have shown that patients in the primary infection stage are estimated to be 26 times more infective than patients in the chronic stage of infection (Hollingsworth et al., 2008), and epidemiological models of immediate antiretroviral therapy (ART) predict a shift from the endemic phase to the elimination phase within five years (Granich et al., 2009), this invention represents a potentially valuable diagnostic tool for clinicians as well as an improvement over the current antibody-based methods of epidemiological research for determining HIV incidence. CRADA Opportunity: The NCI HIV Drug Resistance Program, Host Virus Interaction Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Therapeutic Antibacterial Applications of Phage

Thu, 03 Sep 2009 11:00:00 GMT

The NIH, in collaboration with others, has developed three groups of inventions related to the use of bacteriophages in therapeutic situations. The first group is a method of adapting phages to survive in the body substantially longer than wild-type phages, using serial passaging and/or genetic engineering. The second group involves phages designed to bind the toxins and cytokines that killed bacteria release into the bloodstream, reducing the pathogenic properties of the bacteria. The third group is a method of engineering a phage to have multiple binding sites, such that a single phage can target multiple types of bacteria. CRADA Opportunity: The NCI Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Rapid Diagnostic Applications of Phage

Thu, 03 Sep 2009 15:00:00 GMT

The NIH has available for licensing two techniques for rapid detection of a particular bacteria strain. Similar detection using currently available technologies take 1-2 days; this technology reduces the time to less than one hour. These technologies utilize phage, which has no pathogenic effect on higher plants and animals and are part of approved food-preparation formulations, indicating their known safety profile and an existing regulatory pathway. The first technique involves a phage that incorporates a reporter gene (e.g., luciferase) that will be expressed only when the phage successfully infects a bacterium. This technique is particularly useful where only bacteria-killing ("lytic") phages are known because the method also deactivates the lytic genes, enabling infection and subsequent detection. The second technique involves an engineered phage that will bind with quantum dots upon infection of bacteria; if a sample is treated first with this phage and then with quantum dots, the sample will only respond if the bacteria are present. Both techniques can be used to diagnose a clinical sample (tissue, blood, etc.) or an environmental isolate. CRADA Opportunity: The NCI Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Treatment of Airway Diseases, Including Asthma and COPD, by Targeting Airway Hyperresponsiveness

Wed, 02 Sep 2009 19:00:00 GMT

This technology provides methods of treatment for airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), utilizing molecules that target the airway hyperresponsiveness (AHR) pathway.

Airway diseases are a major health burden in the developed world. A major component of airway disease is airway hyperresponsiveness (AHR), defined as the exaggerated airway constrictive response to external triggers. The inventors have shown that inter-alpha-trypsin inhibitor (IaI), a mammalian protein involved in tissue inflammation and repair, is necessary for the development of AHR, and that inhibitors of IaI prevent the development of AHR. Specifically, the inventors tested their hypothesis that IaI inhibition or absence modifies airway smooth muscle cell binding to hyaluronan, a molecule known to contribute to the response to non-infectious lung injury, which also mediates induced AHR.

Claims in the provisional patent application are directed to methods of treating an airway disease or disorder by administering an inhibitor of IaI, such as an antibody, a polypeptide, a carbohydrate, a small molecule, or an antisense compound. CRADA Opportunity: The NIEHS Division of Intramural Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Elizabeth M. Denholm, Director of the Office of Technology Transfer, at denholme@niehs.nih.gov for more information.

Biomarkers for Sjogren's Syndrome

Wed, 02 Sep 2009 23:00:00 GMT

This technology provides differentially-expressed microRNAs that may be utilized for the development of diagnostics and therapeutics for Sjögren's syndrome.

Sjögren's syndrome is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. The hallmark symptoms of this disorder are dry mouth and dry eyes, but it can also cause serious complications throughout the body. Sjögren's syndrome affects as many as four million people in the United States, making it the second most common autoimmune rheumatic disease. Unfortunately, there is currently no cure for Sjögren's syndrome, nor is there a specific treatment to restore gland secretion. Treatment is generally symptomatic and supportive, including moisture replacement therapies and the use of non-steroidal anti-inflammatory drugs to treat musculoskeletal symptoms. For individuals with severe complications, corticosteroids or immunosuppressive drugs are often prescribed, but these drugs can have serious side effects.

The inventors have identified microRNAs that are differentially expressed in patients with Sjögren's syndrome compared to the normal population; these biomarkers can be used to diagnose Sjögren's syndrome, and are potential targets for treatment of this disease. The inventors have also identified microRNAs associated with high or low salivary flow in this patient population; these markers may serve as targets for therapeutics that restore salivary flow. CRADA Opportunity: The NIDCR is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize differentially-expressed microRNAs. Please contact David Bradley at bradleyda@nidcr.nih.gov.

Immunogenic Tumor-associated Antigen SPANX-B for Selective Cancer Immunotherapy

Thu, 03 Sep 2009 03:00:00 GMT

Researchers at the National Institutes of Health (NIH) have characterized a novel tumor-associated antigen, SPANX-B, that is naturally immunogenic and is expressed in a variety of human malignancies, including melanoma and lung, colon, renal, ovarian and breast carcinomas. In melanoma specifically, SPANX-B expression is associated with advanced and metastatic disease. Moreover, the researchers have found several agonist epitope peptides from SPANX-B which can be used to activate the immune system to eradicate tumors utilizing T cells. SPANX-B peptides have significant clinical and immunotherapeutic potential for the development of cancer diagnostic assays and potent protective and/ or therapeutic vaccines to combat a wide-range of cancers. CRADA Opportunity: The National Institute on Aging, Laboratory of Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of SPANX-B-based therapeutic approaches to combat cancers. Please contact Nicole Guyton, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information.

Monoclonal Antibodies That React With the Capsule of Bacillus anthracis

Mon, 31 Aug 2009 07:00:00 GMT

Bacillus anthracis is the causative agent of anthrax and is surrounded by a polypeptide capsule of poly-gamma-D-glutamic acid (gammaDPGA). gammaDPGA is poorly immunogenic and has antiphagocytic properties. The bacterial capsule is essential for virulence. Antibodies to the capsule have been shown to enhance phagocytosis and killing of encapsulated bacilli. These antibodies in combination with antibodies that neutralize the toxins of B. anthracis could provide enhanced protection by their dual antibacterial and antitoxic activities. Such antibodies would be especially useful for antibiotic-resistant strains.

In order to obtain therapeutically useful anti-gamma DPGA monoclonal antibodies (MAbs), the inventors immunized chimpanzees with conjugates of 15-mer glutamic acid polymers to immunogenic protein carriers (recombinant protective antigen (PA) of B. anthracis). After several immunizations, chimpanzees developed strong immune responses to gammaDPGA. A combinatorial Fab library of mRNA derived from the chimpanzee's bone marrow was prepared and eight (8) distinct Fabs reactive with native gammaDPGA were recovered. Two (2) of the Fabs were converted into full-length IgG with human gamma1 heavy chain constant regions. These two (2) MAbs showed strong opsonophagocytic killing of bacilli in an in vitro assay. These two (2) MAbs were also tested for protection of mice challenged with virulent anthrax spores and results showed that both MAbs provided full or nearly full protection at a dose of 0.3 mg, the lowest dose tested, which is much more potent than previously reported murine anti-PGA MAbs. Since chimpanzee immunoglobulins are virtually identical to human immunoglobulins, these chimpanzee anticapsule MAbs may have clinically useful applications.

This application claims the antibody compositions described above. Also claimed are methods of treating or preventing B. anthracis infection in a mammalian host and isolated polynucleotides comprising a nucleotide sequence encoding the antibodies of the technology. CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize MAbs neutralizing anthrax toxins and capsule for comprehensive protection against anthrax. Please contact Bill Ronnenberg, NIAID Office of Technology Development, at 301-451-3522 for more information.

Antigenic Chimeric Tick-Borne Encephalitis Virus/Dengue Virus Type 4 Recombinant Viruses

Mon, 31 Aug 2009 11:00:00 GMT

The tick-borne encephalitis virus (TBEV) complex is a group of viruses that can cause severe neutrotropic disease and up to thirty percent (30%) mortality. While these viruses can be found in many parts of the world, the largest impact of the disease occurs in Europe and Russia, where approximately fourteen thousand (14,000) hospitalized TBEV cases occur annually. TBEV is in the family Flaviviridae, genus flavivirus and is composed of a positive-sense single stranded RNA genome that contains 5' and 3' non-coding regions and a single open reading frame encoding ten (10) proteins. At present, a vaccine or FDA approved antiviral therapy is not available.

The inventors have previously developed a WNV/Dengue4Delta30 antigenic chimeric virus as a live attenuated virus vaccine candidate that contains the WNV premembrane and envelope (prM and E) proteins on a dengue virus type 4 (DEN4) genetic background with a thirty nucleotide deletion (Delta30) in the DEN4 3'-UTR. Using a similar strategy, the inventors have generated an antigenic chimeric virus, TBEV/DEN4Delta30. This chimeric virus also contains attenuating mutations within the E and nonstructural NS5 proteins. Preclinical testing results with the derived virus indicate that chimerization of TBEV with DEN4Delta30 and introduction of the attenuating mutations decreased neuroinvasiveness and neurovirulence in mice. The TBEV/DEN4delta30 vaccine candidate was safe, immunogenic, and provided protection in monkeys against challenge with TBE viruses.

This application claims live attenuated chimeric TBEV/DEN4Delta30 vaccine compositions. Also claimed are methods of treating or preventing TBEV infection in a mammalian host, methods of producing a subunit vaccine composition, isolated polynucleotides comprising a nucleotide sequence encoding a TBEV immunogen, methods for detecting TBEV infection in a biological sample and infectious chimeric TBEV. CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research in preclinical study of the long-term immunity induced by the TBEV/DEN4 vaccine candidate against highly virulent TBE viruses and in the clinical trials of this vaccine in humans. Please contact Percy Pan, NIAID Office of Technology Development, at 301-496-2644 for more information.

Superior Method of Preparing Dendrimers for Use as Magnetic Resonance Imaging (MRI) Contrast Agents

Tue, 11 Aug 2009 15:00:00 GMT

There is a need to develop more efficient gadolinium-containing (Gd) contrast agents for magnetic resonance imaging (MRI) as the small molecules presently used clinically have the disadvantage of being rapidly cleared from circulation and excreted by the kidneys.

Dendrimer-based macromolecular MRI contrast agents in which numerous chelated Gd ions are covalently attached to a multivalent dendritic architecture are a promising class of diagnostic agents for medical imaging applications. Clinical development of the dendrimer-based agents has been limited as the current methods for synthesizing them result in a complex mixture that produces inconsistent imaging results.

The present technology describes the development of a new method of pre-forming the metal-ligand chelate in alcohol prior to conjugation to the dendrimer. Specifically, for example, a 1B4M-DTPA-Gd chelate is preformed in methanol and purified prior to conjugation to a PAMAM dendrimer molecule. This results in a dendrimer-based MRI contrast agent with greatly improved homogeneity and stability, and possessing an unexpectedly greater molar relaxivity that allows the use of much less of the agent than previously required to obtain comparable images. The use of a DOTA-Gd chelate is equally possible. CRADA Opportunity: The Inorganic & Radioimmune Chemistry Section, ROB, CCR, NCI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize macromolecular (dendrimer-based) MR contrast agents as well as multi-modality analogs. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Multilayered RF Coil System for Improving Transmit B1 Field Homogeneity in High-Field MRI

Tue, 11 Aug 2009 19:00:00 GMT

Available for licensing and commercial development is a multilayered radio-frequency (RF) coil system for improving the transmit B1 field homogeneity for magnetic resonance imaging (MRI) at high field strengths. The current invention aims at manipulating the inhomogeneous profile of the transmit B1 field, which causes MR images to become less uniform as the magnetic field strength is increased, by utilizing an inner array of RF elements (e.g. surface coils) within and coupled to an outer transmit unit (e.g. a birdcage coil or other volume coil). Improvement in B1 field homogeneity is achieved by tuning the surface coils of the inner layer to an appropriate resonant frequency and then passively coupling them to the outer-layer volume coil. Furthermore, the amount of coupling is determined by the intrinsic properties of the transmit unit and can be adjusted accordingly. The current design provides an effective approach for reducing B1 field homogeneity at high fields and can be implemented without the need for independent RF channels, thereby reducing MRI system complexity. Furthermore it can be readily implemented on existing MRI coil systems by detuning surface coils rather than decoupling them during the transmit phase. CRADA Opportunity: The Laboratory of Functional and Molecular Imaging (LFMI) at the National Institute of Neurological Disorders and Stroke (NINDS) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize MRI applications that aim to provide novel functional and molecular imaging techniques to study brain structure and function. Please contact Melissa Maderia, Ph.D. at maderiam@mail.nih.gov or 301-451-3943 for more information.

Oligo Microarray for Detection of All Known Mammalian and Avian Pathogenic Viruses

Tue, 11 Aug 2009 23:00:00 GMT

The spectrum of pathogenic viruses of importance in human disease, agriculture and biology is not only large and diverse, but continually evolving. The identification or isolation of viral pathogens, in correlation with the presence of specific disease phenotypes, is of paramount importance both to diagnosis of disease and the subsequent management or treatment of viral infection. The limitations of current viral detection methods, such as PCR and immunoassays, led to the development of a novel microarray system for specific detection of viruses. The technology offered here for licensing provides a method for high-throughput screening of known pathogenic viruses along with identification of "new" disease-associated viruses.

The novel method is based on a viral microarray containing 10,000 immobilized DNA oligonucleotide features, representing all known mammalian and avian pathogenic viruses (approximately 600). Software was also developed to analyze the viral microarray results. The oligonucleotide features in this system are 60-mer long and distributed across both conserved and non-conserved regions of known viral sequences. This design serves the dual purpose of: (1) facilitating validation via redundant signals associated with each represented virus and (2) allowing for the discovery of new viruses, which arise due to recombination. In addition, positive and negative controls against human and mouse housekeeping genes are included along with software for analysis of virus microarray results.

Further advantages of the viral microarray include: (a) the use of sample inputs as little as 10ng of either total DNA or RNA extracted from virus infected cells, representing as few as 20 viral particles; (b) detection of viruses of both DNA and RNA classes; (c) a capacity for high-throughput screening of various sample types including serum, saliva and biopsy tissues; and (d) analysis of a large number of samples in parallel on identical arrays.

The detection of viral DNA is unique to this technology, as other available technologies only detect viral genomic RNA or viral mRNA transcripts. Additionally, the viral chip was found to be highly specific and sensitive for detecting different viral genomic sequences in cell lines and multiple viral constructs co-infection in cultured cells. CRADA Opportunity: The NCI Laboratory of Molecular Technology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this oligo microarray for identification and detection of all known mammalian and avian pathogenic viruses. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods for Treating or Ameliorating Fibrosis by Inhibiting the Interaction between IL-21 Receptor (IL-21R) and IL-21

Thu, 30 Jul 2009 03:00:00 GMT

This invention includes methods for treating or ameliorating fibrosis by inhibiting the interaction between IL-21 Receptor (IL-21R) and IL-21 using either anti-IL-21R monoclonal antibodies (or binding fragments of anti-IL-21R mAbs), anti-IL-21 monoclonal antibodies (or binding fragments of anti-IL-21 mAbs) or soluble IL-21R (or binding fragments of IL-21R). It is believed that the TH2 immune response, induced by IL-21, plays a major role in the in the pathogenesis of tissue fibrosis. Antagonism of IL-21R by anti-IL-21R monoclonal antibodies or the sequestration of IL-21 by soluble IL-21R or anti-IL-21 monoclonal antibodies has been demonstrated to reduce TH2 immune responses associated with fibrosis in animal models.

The causes of chronic tissue fibrosis are diverse and the market for a therapeutic that targets fibrosis is large. Fibrosis is associated with diverse causes which include: genetic diseases (such as cystic fibrosis); autoimmune diseases (such as scleroderma); chronic viral infections (such as hepatitis), parasitic infections (such as schistosomiasis); and occupational exposures to causative agents (such as asbestosis). Additionally, many cases of tissue fibrosis are idiopathic. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this invention. Please contact Nicole Mahoney at 301-435-9017 or mahoneyn@niaid.nih.gov for more information.

Treatment of Cancer Using Metal Coordinating Compounds that Kill Multi-Drug Resistant Cancer Cells

Wed, 29 Jul 2009 07:00:00 GMT

One of the major hindrances to successful cancer chemotherapy is the development of multi-drug resistance (MDR) in cancer cells. MDR is frequently caused by the increased expression or activity of ABC transporter proteins in response to the toxic agents used in chemotherapy. Research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects, restricting their usefulness as therapeutics.

In an alternative approach to reducing the debilitating effects of MDR during cancer therapy, scientists at the NIH have identified a family of compounds whose activities are enhanced, rather than decreased, in MDR cancer cells. Particular embodiments of these "MDR-selective compounds" include certain metal coordinating compounds. Recent evidence suggests that these MDR-selective compounds can be used to kill cancer cells that overexpress ABC transporters or to re-sensitize multi-drug resistant cancer cells to chemotherapeutics. Furthermore, the effectiveness of these compositions in killing MDR cancer cells correlates directly with the level of ABC transporter expression. Importantly, MDR-selective compounds are not inhibitors of ABC transporters, thereby reducing the likelihood of undesirable side-effects during treatment. Thus, MDR-selective compounds represent a powerful strategy for treating multi-drug resistant cancers as a direct chemotherapeutic and as agents that can re-sensitize MDR cancer cells for treatment with additional chemotherapeutic agents. CRADA Opportunity: The Institute of Enzymology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize MDR-selective compounds. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Truncated Methanocarba Adenosine Derivatives as A₃ Adenosine Receptor Antagonists

Wed, 29 Jul 2009 11:00:00 GMT

Novel A₃ adenosine antagonists available for licensing. A₃ receptors are particularly highly expressed in inflammatory cells, making it a potentially desirable target for inflammatory diseases. This technology relates to highly specific antagonists and partial agonists of A₃ adenosine receptors, which are negatively coupled to adenylate cyclase and have been broadly implicated in inflammation, cardiovascular disease, and cancer. Further, A₃ adenosine receptors have been implicated in allergies, asthma, and chronic obstructive pulmonary disease. CRADA Opportunity: The NIDDK, Laboratory of Bioorganic Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize A₃ adenosine receptor antagonists. Please contact Kenneth A. Jacobson, Ph.D. at kajacobs@helix.nih.gov or the NIDDK Office of Technology Transfer and Development at 301-451-3636 for more information.

A Tumorigenic MEF/3T3 Tet-Off Mouse Fibroblast Cell Line Stably Transfected with a T7-Tagged Srp20 Expression Construct (pJR17)

Wed, 29 Jul 2009 15:00:00 GMT

Alternative RNA splicing is a means by which the human genome can produce many more proteins from the genes available. It is emerging that aberrations in alternative RNA splicing contributes to the development of cancers. SRp20 is a cellular splicing factor that is involved in the process of alternative splicing of RNA. Investigators at the National Cancer Institute (NCI), National Institutes of Health (NIH) have discovered that SRp20 is overexpressed in many types of cancer and furthermore promotes the induction and maintenance of tumor cell growth. This was demonstrated in part by engineering a non-tumorigenic cell to become tumorigenic in mice by overexpressing SRp20.

Research Material available for licensing is a tumorigenic MEF/3T3 tet-off mouse fibroblast cell line stably transfected with a T7-tagged SRp20 expression construct (pJR17) that is under the transcriptional control of tetracycline. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, HIV and AIDS Malignancy Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize A Tumorigenic MEF/3T3 Tet-Off Mouse Fibroblast Cell Line Stably Transfected with a T7-Tagged Srp20 Expression Construct (pJR17). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

High-yield Methods of Producing Biliverdin

Wed, 29 Jul 2009 19:00:00 GMT

This invention describes methods of making high yields of biliverdin, the pharmaceutical compositions of biliverdin made using that process, and methods of using the compositions therapeutically.

In reaction to a wide range of cellular stresses, hemoglobin is naturally metabolized to biliverdin, which is then quickly metabolized to bilirubin, a bile pigment, through a highly conserved set of enzymes. Both bilirubin and biliverdin are normally processed for rapid excretion, and excessive serum levels of bilirubin have known toxic effects (most notably jaundice). Surprisingly, research in the past decade has shown that decreasing serum levels correlate inversely with the prognosis of various disorders, such as ischemia/reperfusion injuries, atherosclerosis, organ transplantation, and several autoimmune diseases. Indeed, in animal-model studies, inducing a mild case of jaundice actually improved outcome. Unfortunately, bilirubin is relatively insoluble, and so is not a practical pharmaceutical itself.

Biliverdin has lower direct toxicity and substantially greater solubility than bilirubin, and also appears to have some direct therapeutic effects similar to bilirubin. Accordingly, biliverdin has been widely studied lately. Generating high yields of pure biliverdin is difficult, however, because any system with the enzymes to break down hemoglobin also has enzymes converting biliverdin to bilirubin. The inventors have created a system of generating microorganisms (yeast) lacking the enzymes that break biliverdin down to bilirubin. CRADA Opportunity: The Laboratory of Pathology in the Center for Cancer Research of the National Cancer Institute is seeking parties interested in collaborative research directed toward clinical applications of biliverdin. For more information about the research, please contact either Dr. Michael Pendrak (NCI/CCR Laboratory of Pathology) at (301) 496-6264, or Dr. April Franks (NCI Technology Transfer Center) at (301) 496-0477.

Mouse Monoclonal Antibody Targeting Tetanus Toxin Heavy Chain Fragment C

Tue, 14 Jul 2009 23:00:00 GMT

The FDA is pleased to announce as available for licensing a murine monoclonal antibody that specifically binds to Fragment C of tetanus toxin. Tetanus toxin is one of the most potent neurotoxins known. It is a complex molecule, composed of a linked heavy chain and light chain, each having different domains serving different functions. One domain of the heavy chain, known as "Fragment C," is known to bind the toxin to neurons. Fragment C is the focus of much research, including: analysis of the subtle differences between neuronal uptake of tetanus toxin and the related botulinum toxin, the design of compounds that block the uptake of tetanus toxin, and design of drugs that target the same cellular mechanism to enhance uptake. CRADA Opportunity: The FDA's Office of Biotechnology Products in the Center for Drug Evaluation and Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antibodies directed against tetanus toxin. Please contact Alice Welch, Ph.D. at 301-827-0359 or Alice.Welch@fda.hhs.gov for more information.

High Diversity/High Affinity Domain Antibody Library

Wed, 15 Jul 2009 03:00:00 GMT

Available for licensing and commercial development is a highly diverse domain antibody (dAb) library providing antibodies that bind with high affinity to variety of antigen targets. Antibody diversity is inherently limited by using only three CDRs of either light chain variable domain (LCDRs) or heavy chain variable domain (HCDRs). This novel dAb library is designed using light chain variable domain 3 (LCDR3) and heavy chain variable domain (HCDR3), which are of primary importance for creating binding site diversity in the human immune system. The library contains 2.5 x 10¹⁰ dAbs. Human naturally occurring LCDR3s were grafted onto HCDR1 of m0. These antibodies are of very small size (15-17 kDa), high stability and can be expressed at high levels as monomers. The library can be used for the selection of antibodies to any antigen including cancer and viral antigens and exhibit such properties as good penetration, stability, solubility, high levels of expression (at potentially low cost), and low level of immunogenicity or toxicity. CRADA Opportunity: The National Cancer Institute, CCR, CCRNP is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this domain antibody library. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel Dopamine Receptor Ligands as Therapeutics for Central Nervous System Disorders

Wed, 08 Jul 2009 07:00:00 GMT

The dopamine D3 receptor subtype is a member of the dopamine D2 subclass of receptors. These receptors have been implicated in a number of CNS disorders, including psychostimulant abuse, psychosis and Parkinson's disease. Compounds that bind with high affinity and selectivity to D3 receptors can not only provide important tools with which to study the structure and function of this receptor subtype, but may also have therapeutic potential in the treatment of numerous psychiatric and neurologic disorders.

The 4-phenylpiperazine derivatives are an important class of dopamine D3 selective ligands. However, due to their highly lipophilic nature, these compounds suffer from solubility problems in aqueous media and reduced bioavailability. To address this problem, a process was designed to introduce functionality into the carbon chain linker of these compounds. Compared to currently available dopamine D3 receptor ligands, the resulting compounds show improved pharmacological properties and D3 selectivities but due to their more hydrophilic nature, these derivatives are predicted to have improved water solubility and bioavailability. CRADA Opportunity: The National Institute on Drug Abuse's Medications Discovery Research Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize 4-phenylpiperazine derivatives as dopamine D3 selective ligands. Please contact VioConley, M.S. at 301-435-2031 or conleyv@mail.nih.gov for more information.

Therapeutic Applications of a p53 Isoform in Regenerative Medicine, Aging, and Cancer

Thu, 02 Jul 2009 11:00:00 GMT

p53 plays a critical role in carcinogenesis and aging as a key regulator of cell cycle progression, senescence and apoptosis. The inventors have discovered that a natural variant of p53 (delta133p53) inhibits p53-dependent cell senescence. Utilizing delta133p53 siRNAs, the inventors have data demonstrating that siRNA-treated human fibroblast undergo cell senescence, thereby indicating that delta133p53 inhibition could be a novel approach for cell senescence-mediated anti-proliferative therapy, including anti-cancer treatments. Alternatively, enhanced expression with delta133p53 can extend the replicative lifespan of normal human cells. This technology may provide a new method in the field of regenerative medicine for aging-related degenerative disease.

Also available for licensing are delta133p53 siRNAs and shRNA vectors, as well as a delta133p53 overexpression vector, which can be used for cancer and age-related degenerative therapeutics. The shRNA can be stably integrated into the cellular genome for long-term delta133p53 inhibition.

The inventors have also discovered that another p53 variant (p53beta) accelerates p53-dependent cell senescence, and developed a vector for overexpressing p53beta, which could be used for cell senescence-mediated anti-proliferative therapy. CRADA Opportunity: The National Cancer Institute, Laboratory of Human Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Curtis_Harris@nih.gov for more information.

Gene Expression Signature Predictive of Response to Chemotherapy

Thu, 02 Jul 2009 15:00:00 GMT

Combination cisplatin and fluorouracil (CF) is a reference chemotherapy regimen for metastatic gastric cancer. However, to date, no genome-wide studies have identified distinctions in gene expression that predict which subjects with metastatic disease will benefit from this therapy and which subjects will not exhibit a therapeutic response to chemotherapy. Given the toxicity of chemotherapy, however, defining parameters that identify those subjects who will likely benefit from chemotherapy is of paramount importance. Early identification of non-responders would provide opportunities to explore alternate or novel therapeutic approaches. Thus, a need exists to identify methods of predicting a subject's response to chemotherapy prior to receiving the treatment.

Scientists at the National Institutes of Health have discovered a three-gene signature that can be used to determine the chemotherapy response in patients with cancer. By measuring the expression of three cancer-specific genes it can be determined if a patient with an epithelial cancer such as gastric, bladder, head and neck, esophageal or cervical cancers, will respond to CF treatment. The inventors have demonstrated that examining these expression levels has high fidelity in identifying CF treatment non-responders. Further, the invention describes a mechanism that can help patients identified as non-responders become responsive to treatment. Therefore these methods have the potential to reduce fatalities caused by metastatic gastric cancer by identifying patients early on who are non-responsive to standard CF treatment and customizing a new treatment plan which may be better suited to their individual needs. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Cancer Biology and Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Gene Expression Signature Predictive of Response to Chemotherapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Immunogenic Peptide from NGEP Protein for Developing Prostate Cancer Vaccines

Thu, 02 Jul 2009 19:00:00 GMT

The NGEP protein is only present in the prostate and is typically overexpressed on prostate cancer cells. Hence, as a novel prostate tumor-associated antigen (TAA) it is a good target for developing active immunotherapies to kill prostate cancer cells. For example, NGEP could be used in a vaccine to activate an individual's immune system to recognize and kill NGEP-expressing prostate cancer cells. However, TAAs typically are not very effective in inciting an immune response. This can be overcome by identifying portions (epitopes) of the TAA that are more immunologically active.

Investigators at the NIH have identified a small peptide fragment of the NGEP protein (NGEP CTL peptide epitope) that is very effective in activating cytotoxic lymphocytes causing them to destroy prostate cancer cells and has great potential for development of a variety of active immunotherapy strategies, such as vector-based cancer vaccines, to treat and prevent prostate cancer. In addition, it could be used for developing sensitive immunoassays for measuring the immune response of a prostate cancer patient during immunotherapy. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Tumor Immunology and Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Kevin Brand, J.D. at 301-451-4566 or brandk@mail.nih.gov for more information.

The Protein Cyanovirin Inactivates HIV and Influenza

Thu, 02 Jul 2009 23:00:00 GMT

Cyanovirin-N (CV-N) potently and irreversibly inactivates diverse primary strains of HIV-1, including M-tropic forms involved in sexual transmission of HIV, as well as T-tropic and dual-tropic forms. CV-N also blocks cell-to-cell transmission of HIV infection. CV-N interacts in an unusual manner with the viral envelope, binding with extremely high affinity to poorly immunogenic epitopes on gp120. Further, CV-N and homologous proteins and peptides potently inhibit diverse isolates of influenza viruses A and B, the two major types of influenza virus that infect humans.

The described technology includes glycosylation-resistant mutants, which code sequences to enable ultra large-scale recombinant production of functional CV-Ns in non-bacterial (yeast or insect) host cells or in transgenic animals or plants. Therefore, these glycosylation-resistant mutants may allow industry to produce CV-Ns on a large scale and make CV-Ns cheap enough for developing countries to benefit from this invention.

CV-N was benign in vivo when tested in the rabbit/monkey vaginal toxicity/irritancy model and was not cytotoxic in vitro against human immune cells and lactobacilli. CV-N is readily soluble in aqueous media, is remarkably resistant to physicochemical degradation and is amenable to very large-scale production by a variety of genetic engineering approaches. CRADA Opportunity: The National Cancer Institute, Molecular Targets Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Modulators of Pregnane X Receptor (PXR) as Therapeutics for Bowel Disorders (BD)

Fri, 03 Jul 2009 03:00:00 GMT

This technology is based on the novel findings that susceptibility to BD is strongly associated with genetic variation in the PXR gene, a member of the nuclear receptor family, and rifaximin is a specific activator of human PXR. PXR is an integral component of the body's defense mechanism involved in endogenous and xenobiotic detoxication. Based on these novel findings, the present technology provides a) methods of screening for compositions that modulate inflammatory bowel disease (IBD), b) methods of inhibiting inflammation of the bowel and related tissues and organs, and c) methods of treatment of inflammatory bowel disease. CRADA Opportunity: The Laboratory of Metabolism, Center for Cancer Research, NCI, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize compounds that ameliorate bowel disorders through the PXR pathway. Please contact Lisa Finkelstein, Ph.D. at 301-451-7458 or lfinkels@mail.nih.gov for more information.

A Locking Device for Permanently Securing Surgical Suture Loops

Thu, 02 Jul 2009 07:00:00 GMT

This technology relates to a device that can be used to non-invasively secure surgical suture loops when combined with a percutaneous delivery system. It has been shown to be effective in correcting mitral valve regurgitation (MVR) in an animal model. During the procedure, a guidewire is percutaneously conveyed to the atrium of the heart and is used to secure the "cerclage" suture encircling the mitral valve annulus, which is delivered using a delivery catheter. The locking device is advanced over the suture by the delivery catheter and it permanently secures the suture and maintains the tension on the annulus once the delivery system is removed. This locking device, in combination with the percutaneous procedure, allows for more complete coaptation of the valve leaflets and correction of MVR without the need for open heart surgery and its associated risks. The locking device is also adjustable, allowing the user to vary the tension on the suture if further tightening or loosening is required. It is also MRI compatible and all follow-up studies can be performed under MRI.

This invention has demonstrated its ability to correct MVR in animals where the locking device was observed to maintain the correct position and tension after implantation. This device has the potential to replace the traditional loop and knot method used for surgical correction of MVR, and may also be useful for other conditions that require permanently secured suture loops. CRADA Opportunity: The National Heart Lung and Blood Institute Cardiac Catheterization Lab is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the tension fixation device. Please contact Peg Koelble at 301-594-4095 or koelblep@nhlbi.nih.gov for more information.

Novel Compounds that Specifically Kill Multi-Drug Resistant Cancer Cells

Thu, 02 Jul 2009 11:00:00 GMT

One of the major hindrances to successful cancer chemotherapy is the development of multi-drug resistance (MDR) in cancer cells. MDR is frequently caused by the increased expression or activity of ABC transporter proteins in response to the toxic agents used in chemotherapy. Research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects, restricting their usefulness as therapeutics.

Investigators at the NIH previously identified that the compound NSC73306 had the ability to specifically kill cancer cells that overexpressed an ABC transporter responsible for MDR. Importantly, this "MDR-selective compound" is not an inhibitor of ABC transporters, reducing the likelihood of undesirable side-effects if used as a therapeutic.

Using NSC 73306 as a model, new MDR-selective compounds have been created with improved solubility and selectivity. These new MDR-selective compounds can also selectively kill MDR cancer cells, with their efficacy correlating directly with the level of ABC transporter expression. Recent evidence also shows that these new MDR-selective compounds have the ability to decrease the expression of ABC transporters, potentially re-sensitizing the cancer cells to chemotherapeutic agents. Thus, MDR-selective compounds represent a powerful strategy for treating multi-drug resistant cancers as a direct chemotherapeutic and as agents that can re-sensitize MDR cancer cells for treatment with additional chemotherapeutic agents. CRADA Opportunity: The National Cancer Institute, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the agents described here. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Differentiation of Human Embryonic Stem Cells into Dopaminergic Nerve Cells

Tue, 23 Jun 2009 15:00:00 GMT

The invention described here is a novel method of differentiating human embryonic stem cells (hESCs) into dopaminergic nerve cells, which is preferable to the currently available dopaminergic differentiation techniques.

This invention potentially provides a source of sufficient dopaminergic cells not only for the clinical transplantation of dopaminergic tissue but also for in vitro studies of human cells useful for pharmaceutical screens related to neurodegenerative disorders and substance abuse.

Neurodegenerative disorders encompass a range of debilitating conditions including Parkinson's disease, Alzheimer's disease, and Huntington's disease. The primary cause of cognitive dysfunction for these three disorders has been directly linked to neuron degeneration, usually in specific areas of the brain. Transplantation of fetal dopaminergic neurons in affected areas of the brain in late stage Parkinson's disease has demonstrated clinical utility in human patients. However, fetal transplantation therapy generally requires human tissue from at least 3-5 embryos to obtain a clinically reliable improvement in the patient, thus demonstrating a need for a larger and more reliable source of dopaminergic cells. HESCs are a promising alternative source of cells because they can grow in culture indefinitely and have the ability to differentiate into a variety of cell types. One of the most efficient methods for conversion of hESCs to dopaminergic neurons requires the presence of mouse stromal cells which have an undefined dopaminergic inducing activity. However, the major disadvantage of this method is the exposure of hESC to mouse cells, which hinders any downstream clinical application due to possible transfer of animal cells and pathogens. This invention has unveiled the molecular nature of the activity of the mouse cells and established an efficient alternative approach for dopamine neuron generation, which is more suitable for clinical application. This innovative approach potentially provides a large and reliable source of dopaminergic cells sufficient for clinically relevant transplantation of dopaminergic tissue as well as in vitro pharmacologic studies of human dopaminergic cells. CRADA Opportunity: The National Institute on Drug Abuse, Development and Plasticity Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Vio Conley, M.S. at 301-496-0477 or conleyv@mail.nih.gov for more information.

Inflammatory Genes and MicroRNA-21 as Biomarkers for Colon Cancer Prognosis

Tue, 23 Jun 2009 19:00:00 GMT

Colon adenocarcinoma is the leading cause of cancer mortality world-wide and accounts for approximately 50,000 deaths annually in the United States. Adjuvant therapies improve survival for stage III colon cancer patients; however, it remains controversial if stage II patients should be given these therapies. Some stage II patients will benefit from therapy (such as patients with undetectable micro-metastases where surgery will not be curative); but therapy for others will harm quality of life with little therapeutic benefit (such as patients where surgery removed all cancerous tissue and therefore do not need additional therapy). Thus, there is a need to for biomarkers capable of accurately identifying high risk, stage II patients that are suitable for therapeutic intervention.

The investigators have identified an inflammatory gene and microRNA biomarker portfolio that can predict aggressive colon cancer, colon cancer patient survival, and patients that are candidates for adjuvant therapy. These biomarkers provide clinicians with a powerful tool to diagnose colon cancer patients and chose effective treatment methods. CRADA Opportunity: The NCI Laboratory of Human Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cancer biomarkers and therapeutic targets. Please contact Curtis_Harris@nih.gov for more information.

A Novel System for Producing Infectious Hepatitis C Virus (HCV) Virions and Development of a Novel Reporter System for Studying HCV Entry

Tue, 23 Jun 2009 23:00:00 GMT

HCV has infected an estimated 3% of the world population in whom viral infection persists for more than two third of the cases, often resulting in life-threatening complications. The standard of care (pegylated interferon alpha-2 plus ribavirin) is efficient in only 50% of treated patients, costly and has numerous side effects. In addition, viral resistance to newly developed drugs -- targeting viral protease or RNA polymerase -- has been described, but no vaccine is yet available. The difficulty in developing HCV vaccines is largely due to the broad sequence-diversity displayed by HCV, the frequent occurrence of viral mutations within immunogenic epitopes in vivo, and the lack of proper standard/definition for viral neutralization.

One alternative strategy in HCV-vaccine or drug development comprises measuring viral entry, the first step in viral infection. Such measurements are limited by the available screening systems, in that, HCV pseudo-typed retroviral particles have a different envelope conformation and contain foreign components that are likely to interfere with the measured HCV entry. Moreover, HCV lab strain requires intensive replication for its in vitro production, resulting in numerous mutations that impede development of convenient screening tools.

The inventors have developed a system for generating infectious HCV particles and HCV-like particles (HCV-LP) suitable for a qualitative single-cycle entry assay, completely independent of HCV replication. To adapt this system as a single assay to study HCV-LP entry, HCV non-structural genes were replaced with a heterologous gene that upon viral-entry triggers firefly luciferase and EGFP expressions in target as well as non-permissive cells. The pretreatment of HCV-replication permissive HuH-7.5 cells with siRNA targeting HCV candidate receptors inhibited viral entry. These new systems enable production of authentic HCV infectious particles as well as HCV-LPs suitable for single-cycle entry assays adaptable to high throughput screening. CRADA Opportunity: The NIAID OTD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a novel system for producing infectious HCV virions and developing a reporter system for studying HCV entry. Please contact Michael Piziali at 301-496-2644 for more information.

Increasing the Effectiveness of Cancer Treatment: T Cell Receptors Designed to Release Interleukin-12 Specifically at Cancer Sites

Wed, 24 Jun 2009 03:00:00 GMT

Many conventional chemotherapy drugs currently utilized to treat cancer also yield harsh side effects in patients. In addition, many patients do not respond to generalized chemotherapy and radiation treatments for cancer. There is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity in individual patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual's innate and adaptive immune system to fight against specific diseases, including cancer.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response.

Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to express the human interleukin 12 (IL-12) cytokine only in the tumor environment. Specifically, these T cells have been designed to express a human IL-12 gene under the control of the nuclear factor of activated T cells (NFAT) promoter. When the TCR on these T cells recognizes a tumor antigen, IL-12 expression is induced through activation of the NFAT promoter. Thus, IL-12 is only released at the cancer site and only after the activation of the T cell. This technology makes it possible to control the expression of IL-12 to enhance T cell cytolytic activity while also reducing or eliminating the IL-12 toxicity observed with other IL-12 related therapies. Infusing these IL-12 expressing T cells into patients via adoptive immunotherapy could prove to be powerful new tools for attacking tumors. CRADA Opportunity: The National Cancer Institute, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adoptive immunotherapies or the development of cancer therapeutics based on the use of T cell receptors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of MMP-8 as a Prognostic Marker for Melanoma

Mon, 08 Jun 2009 07:00:00 GMT

Cutaneous malignant melanoma is the most common fatal skin cancer, and the incidence of this disease increases each year. The average survival time for patients diagnosed with malignant melanoma is less than ten months. Consequently, it is important to identify and understand genetic alterations leading to malignant melanoma so that new treatments strategies can be developed.

Matrix Metalloproteinases (MMPs) have been associated with increased metastasis and several small molecule inhibitors have been developed as potential anticancer agents. Unfortunately, these inhibitors have been largely unsuccessful despite the research suggesting otherwise and it is clear that additional analyses are warranted. The NIH inventors have recently performed a mutational analysis of the MMP gene family in human cutaneous metastatic melanoma and have identified several novel somatic mutations, most notably mutations in MMP-8. This invention provides methods of identifying specific inhibitors to MMP-8 that could be used to treat patients with MMP-8 mutations. It also provides methods for predicting the prognosis of patients with MMP-8 mutations. Thus, this invention could not only help identify the roles of specific MMPs in melanoma, but also help further the development MMP inhibitors to treat melanoma patients. CRADA Opportunity: The National Human Genome Research Institute’s Cancer Genetics Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, and/or commercialize this newly identified candidate melanoma diagnostic and prognostic marker as well as to identify and develop possible MMP-8 activators for testing as possible anti-melanoma agents. Please contact NHGRI’s Technology Development Coordinator (TDC) Claire T. Driscoll at cdriscol@mail.nih.gov for more information.

Mouse Model of Individual Unresponsive to Interferon

Mon, 08 Jun 2009 11:00:00 GMT

NIAID has developed a mouse model that produces very high levels of Interferon-alpha-receptor 2 (IFNAR2), both in liver cells and free-floating in serum.

Chronic co-infection of HIV and hepatitis C virus (HCV) is associated with increased overall morbidity and mortality compared to those infected with just one virus. Recent data further suggests that co-infection is also associated with a more rapid progression of liver disease, higher HCV RNA viral levels, decreased cure rate of HCV, and increased toxicities of anti-HCV therapy. Finally, clinical trials have shown that many patients infected with both viruses do not respond to Interferon-based therapy. Research strongly suggests that non-responding patients have an increased level of a free-floating form of IFNAR2, which could block Interferon activity.

Resistance to Interferon therapy also occurs in other diseases, such as autoimmune diseases (e.g., lupus, scleroderma, psoriasis, vasculitis) and certain forms of cancer (e.g., Kaposi’s sarcoma, follicular lymphoma). The various means by which resistance arises is currently being researched. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, is interested in collaborative research directed toward molecular strategies for vaccine and antiviral development, and animal models of viral hepatitis C. Please contact William Ronnenberg at 301-451-3522 or wronnenberg@niaid.nih.gov for more information.

Improved Antibodies Against ErbB4/Her4

Mon, 08 Jun 2009 15:00:00 GMT

ErbB4/Her4 is a receptor tyrosine kinase that regulates cell proliferation, cell differentiation and cell survival. ErbB4 has been implicated in the pathology of numerous cancers (e.g., breast cancer, non-small cell lung carcinoma, adenocarcinoma), as well as psychiatric disorders (e.g., schizophrenia). As a result, ErbB4 is an excellent target for developing therapies against these diseases. Unfortunately, the study of ErbB4 has been slowed by the lack of highly specific and functional antibodies against the receptor.

In order to overcome the deficiencies with current ErbB4 antibodies, NIH inventors have generated three rabbit monoclonal antibodies with improved properties and versatility. Specifically, the mAb-6, mAb-7 and mAb-10 hybridomas produce antibodies with a high degree of specificity and affinity for ErbB4. These antibodies recognize specific epitopes on the intracellular domains of ErbB4 without cross-reaction against other proteins, and can be used successfully in the immunostaining of fixed tissue. Each antibody recognizes both human and mouse ErbB4, whereas only mAb-7 and mAb-10 recognize rat ErbB4. CRADA Opportunity: The Eunice Kennedy Shriever National Institute of Child Health and Human Development, Section on Molecular Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further evaluate or commercialize specific rabbit monoclonal antibodies generated against the ErbB4 receptor (also known as HER4). Please contact Joseph Conrad III, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information.

Self-Expanding Stent for Valve Replacement

Mon, 01 Jun 2009 19:00:00 GMT

Aortic stenosis and aortic regurgitation are the most common types of aortic valvular diseases. Such diseased aortic valves in the body are traditionally replaced with valve prosthesis by an open surgical implantation. Available for licensing and commercial development is intellectual property covering stents for use with valve prostheses. As illustrated below, one possible embodiment of the invention includes a self-expandable stent with an elastic tubular latticework having radial and longitudinal direction. The stent geometry and mechanical parameters provide more anatomically-correct placement and the flexible scaffolding of the valve (using an interconnected four-sided polygons and longitudinal rods comprising a self-expanding stent with a plurality of struts connecting a plurality of rods) allow for secure implantation with adaptable apposition of the prosthesis in the aorta.

CRADA Opportunity: The National Heart, Lung, and Blood Institute, Cardiothoracic Surgery Research Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Peg Koelbe at 301-594-4095 or koelblep@nhlbi.nih.gov for more information.

New Weapons to Attack Cancer: T Cell Receptors Designed to Recognize Tumors with Enhanced Affinity

Thu, 28 May 2009 23:00:00 GMT

Given the unpleasant side-effects associated with many cancer drugs, there is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual's innate and adaptive immune system to fight against specific diseases, including cancer.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins.

Scientists at the National Institutes of Health (NIH) have developed T cells with an enhanced ability to recognize the tumor associated antigens (TAAs) NY-ESO-1 and MART-1. These T cells were engineered to increase their ability to recognize these TAAs by making small genetic modifications to the TCRs that recognize these TAAs. NY-ESO-1 is a cancer-testis antigen found in normal testis and various tumors. MART-1 is a melanoma antigen found on normal melanocytes and overexpressed in malignant melanomas. Previous versions of gene-modified T cells developed by these researchers to attack tumors demonstrated objective clinical responses in some cancer patients, which validated gene-modified T cell adoptive immunotherapy as a promising cancer treatment strategy. These latest versions of the NY-ESO-1 and MART-1 specific TCRs, designated 1G4 NY-ESO-1 and DMF5 MART-1, were rationally engineered to enhance anti-tumor activity. These TCRs cause T cells to exhibit enhanced cytokine production and increased lysis of tumor cells when stimulated with NY-ESO-1 or MART-1. Infusing these T cells into patients via adoptive immunotherapy could prove to be powerful new tools for attacking tumors. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize TCRs that enhance the function of gene-modified T cells. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

T Cells Attacking Cancer: T Cell Receptors that Recognize the Tyrosinase Tumor Antigen

Fri, 29 May 2009 03:00:00 GMT

A problem with current chemotherapy-based cancer treatments is the harsh side-effects associated with many cancer drugs. Thus, there is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity. Adoptive cell transfer (ACT) is a promising new immunotherapeutic approach to treat cancer and other diseases by directing an individual's innate and adaptive immune system to recognize specific disease-associated antigens.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins.

Scientists at the National Institutes of Health (NIH) have isolated T cells that recognize the human tyrosinase tumor-associated antigen (TAA) from the tumor infiltrating lymphocytes (TIL) of a melanoma cancer patient. The human tyrosinase antigen is a tumor antigen expressed in a variety of cancers, including skin cancer (melanoma) and brain cancer (glioblastoma). Utilizing the tyrosinase specific T cells, these scientists developed human/mouse hybrid TCRs with enhanced affinity for the tyrosinase TAA. The TCR sequences were modified by making specific amino acid substitutions and replacing certain TCR regions with mouse homologues. These TCRs also showed CD8-independency and, thus, can be expressed in both CD8 and CD4 T cells. T cells expressing these engineered TCRs recognize skin and brain tumor cells in culture. These T cells also exhibit enhanced cytokine induction and better tumor reactivity compared to unmodified TCRs. Previous versions of gene-modified T cells developed by NIH researchers demonstrated objective clinical responses in some cancer patients, which have validated gene-modified T cell immunotherapy as a promising cancer treatment strategy. TCRs directed against the tyrosinase TAA could serve as valuable new immunotherapeutic tools for attacking tumors, especially in patients whose tumors do not express other common TAAs. CRADA Opportunity: The National Cancer Institute, Surgery Branch, Tumor Immunology Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize T Cells Attacking Cancer: T Cell Receptors that Recognize the Tyrosinase Tumor Antigen. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Diagnostic Markers for Melanoma

Thu, 28 May 2009 07:00:00 GMT

This invention relates to diagnostic and prognostic markers for melanoma. It discloses the identification of somatic mutations in genes of the microphthalmia-associated transcription factor (MITF) pathway in patients with melanoma.

Melanoma is an aggressive and often fatal cancer with increasing incidence worldwide. Previous studies have linked the MITF pathway to the progression of melanoma. However, little is known about somatic mutations in genes of the MITF pathway that contribute to the development and progression of melanoma. To assess the role of the MITF pathway in melanoma, NIH investigators evaluated primary and metastatic melanoma samples for the presence of somatic mutations in two genes of the MITF pathway, MITF and SRY (sex determining region Y)-box 10 (SOX10). They identified 16 previously unidentified somatic mutations in these genes. These studies suggest that MITF and SOX10 genes be used as diagnostic markers in human metastatic melanoma. CRADA Opportunity: The National Human Genome Research Institute's Cancer Genetics Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these newly identified candidate melanoma diagnostic and prognostic markers. Please contact NHGRI's Technology Development Coordinator (TDC) Claire T. Driscoll at cdriscol@mail.nih.gov for more information.

Method for the Diagnosis and Prognosis of Age-Related Cardiovascular Disorders

Thu, 28 May 2009 11:00:00 GMT

NIH investigators have discovered a method for the diagnosis and prognosis of cardiovascular aging. Current methodologies include the measurement of patient lipid profiles or expression of up to two proteins. In contrast, this technology utilizes the expression levels of a panel of proteins not previously known to be related to cardiovascular aging and may prove to be a more accurate diagnostic or prognostic of cardiovascular aging than currently available tests or it may improve the accuracy of currently available tests when used in concert.

The technology relates to methods for determining susceptibility to having an extremely common age-associated vascular disorder. It also describes the subsequent use of these proteins as markers for disease. While the underlying cellular and molecular mechanisms of age-related vascular disease remain largely undefined, the expression levels of the genes described in this technology have been empirically determined to differ between healthy and age-inflamed arterial tissue. Further, this technology includes a companion mass spectroscopic-based methodology for reproducible quantification of specific expression levels of interest. CRADA Opportunity: The National Institute on Aging, Cardiovascular Biology Unit-Vascular Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize idea of how to assess and retard accelerated arterial aging and its attendant risks for atherosclerosis and hypertension. Please contact Vio Conley at 301-496-0477 or conleyv@mail.nih.gov for more information.

Methods for Identifying Breast Cancer Patients for Therapy with mTOR Inhibitors

Thu, 28 May 2009 15:00:00 GMT

This technology relates to methods of identifying individuals with invasive breast cancer who may benefit from treatment with an inhibitor of mammalian Target of Rapamycin (mTOR), particularly those having a gene amplification including chromosome 8p11-12 or a portion thereof. Chromosome 8p11-12 is the second most commonly amplified region in breast cancer cases, after HER2 amplification at chromosome 17. Similar to HER2 amplification, the amplification of 8p11-12 is associated with decreased survival. However, whereas patients diagnosed with HER2 amplifications can be more effectively treated with adjuvant therapy using HER2 inhibitors such as trastuzumab, no specific therapy has been identified for breast cancer patients having an amplification of chromosome 8p11-12.

Investigators at NIH have shown that amplification of chromosome 8p11-12 leads to increased copy number of the gene for eukaryotic translation initiation factor 4E binding protein 1, or EIF4EBP1 and elevated expression of the protein in these breast cancer cell lines. EIF4E is a rate limiting component of a multi-subunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. EIF4EBP1 interacts and inhibits EIF4E complex assembly and thus, represses translation. In breast cancer cell lines with EIF4EBP1 amplification, the elevated EIF4EBP1 is largely inactivated via hyperphosphorylation. As the phosphorylation of EIF4EBP1 is controlled by mTOR, its hyperphosphorylation can be reversed with rapamycin. Indeed, rapamycin is much more effective in inhibiting the formation of active translational complex and the growth of breast cancer cells with chromosome 8p11-12/EIF4EBP1 amplification. Thus, detection of chromosome 8p11-12 amplification, and/or over-expression or increased phosphorylation of EIF4EBP1 can be used to identify breast cancer patients for treatment with inhibitors of mTOR, such as rapamycin or its derivatives or analogs. CRADA Opportunity: The Genetics Branch at National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Inhibitors of CD25 to Treat Autoimmune Diseases and Tumors

Thu, 28 May 2009 19:00:00 GMT

This invention discloses therapeutics for the treatment of Multiple Sclerosis, uveitis, and certain cancers by providing methods and compositions for selectively blocking CD25 on T cells or dendritic cells. The therapeutics developed using the current technologies have the potential to exhibit superior specificity and minimal side-effects. In this invention, NIH investigators, for the first time, demonstrate that mature dendritic cells (mDC) use CD25 for trans-presentation of IL-2, and the blockade of CD25 on the surface of mDCs abrogates T cell proliferation. Further, CD25 expression on T cells is not only dispensable for their proliferation, but it also limits effector T cell survival. These observations form the basis for the development of novel therapies for certain cancers and autoimmune disorders. CRADA Opportunity: The National Institute of Neurological Disorders and Stoke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of treating multiple sclerosis by administering agents that block the interaction of dendritic cells and T cells via CD25. Please contact Dr. Martha Lubet at 301-435-3120 or lubetm@mail.nih.gov for more information.

Broadly Applicable Modules for Improved Expression and Detection of Membrane Proteins

Thu, 28 May 2009 23:00:00 GMT

NIH investigators have designed and tested a set of expression modules that are applicable to a wide variety of membrane proteins. Prior to this invention, cloned membrane proteins have sometimes been difficult to detect due to the lack of effective antibodies. Moreover, currently available expression vectors lack the signal sequences, tags, and multiple cloning sites to clone membrane proteins and express them on the cell surface. This invention is the first of its kind to contain all of these elements to facilitate biochemical studies on membrane proteins.

This technology is a set of nucleic acid modules designed for the expression and tagging of membrane proteins in mammalian cells. The module includes a signal peptide, an exchangeable tag, and a multiple cloning site. The gene of a membrane protein may be conveniently inserted into the multiple cloning site, and the signal peptide will target the cloned membrane protein to the cell surface. The tag, in frame with the signal peptide, is either a fluorescent protein or an epitope for a known antibody, both of which enable detection of the protein by several standard biochemical methodologies. CRADA Opportunity: The National Institute on Aging, Laboratory of Cardiovascular Sciences, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the technology of mammalian membrane protein expression and detection. Please contact Vio Conley at 301-496-0477 or conleyv@mail.nih.gov for more information.

Immortalized Virus-Free Human Placental Cell Lines

Fri, 29 May 2009 03:00:00 GMT

This technology provides immortalized virus-free human placental cell lines. To develop these cell lines, human placental cells were immortalized with adenovirus-origin-minus (ori-)-simian virus-40 (SV40) recombinant viruses containing either wild-type or temperature-sensitive (ts) A mutants of SV40. Cells transformed with the SV40 tsA chimera (HP-A1 and HP-A2), but not the SV40 wild-type chimera (HP-W1), were conditional for transformation. All three cell lines expressed trophoblast-specific genes, including placental specific genes and the alpha- and beta-subunits of hCG.

These immortalized virus-free human placental cell lines expressing major proteins of human trophoblasts provide efficient in vitro models to study placental functions. CRADA Opportunity: The National Institute of Child Health and Human Development, Section on Cellular Differentiation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Immortalized Virus-Free Human Placental Cell Lines. Please contact Joseph Conrad III, Ph.D. at 301-435-3107 or jmconrad@mail.nih.gov for more information.

Novel Method of Treating Cancer Using Ixolaris

Thu, 28 May 2009 07:00:00 GMT

Aggressive tumors spread between tissues in a process known as metastasis. Tumor metastasis, particularly with regard to brain cancer (gliomas), has been linked to the aberrant expression of membrane-bound tissue factor (TF). TF normally functions as a blood coagulation factor and can lead to the production of pro-angiogenesis factors such as vascular endothelial growth factor (VEGF). By doing this in the vicinity of tumors, TF may enhance both tumor growth and the ability of tumors to metastasize.

Ixolaris is a protein that prevents the initiation of blood coagulation, specifically by inhibiting TF. NIH inventors have explored the possibility that Ixolaris could be effective as an anti-cancer therapy. As an inhibitor of TF, Ixolaris could potentially inhibit the function of TF, thereby reducing the ability of a tumor to develop and to metastasize. Recent data show that Ixolaris has the ability to prevent tumor growth in vivo using mouse xenograft models. Importantly, the inhibition in vivo occurred without noticeable bleeding. Since Ixolaris is not immunogenic, it might be an excellent candidate as an anti-cancer therapeutic. CRADA Opportunity: The NIAID, OTD, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Ixolaris for cancer treatment. Please contact Dana Hsu at 301-496-2644 for more information.

Identification of Renal Cell Carcinoma Biomarkers

Fri, 15 May 2009 11:00:00 GMT

This invention describes the identification of potential renal cancer biomarkers which could be utilized in the development of a renal cancer diagnostics. The invention identified cancer protein biomarkers from clinically relevant samples including peripheral blood and fresh frozen tissues. Vast availability of fresh frozen tissues and peripheral blood specimens that are easily obtained could lead to clinical tests amenable to therapeutic, prognostic and even early screening tests for renal cell carcinoma and other malignancies. CRADA Opportunity: The National Cancer Institute Laboratory of Proteomics and Analytical Technologies is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostic, therapeutic and prognostic cancer biomarkers from clinical specimens. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Simple Biosensors Based on Electrical Percolation Biological Semiconductors

Fri, 15 May 2009 15:00:00 GMT

The invention offered for licensing is in the field of biosensors with application in diagnostics and in regulation of implantable biomedical devices. More specifically, it is related to biological semiconductors based on the electrical percolation of single-walled carbon nanotubes (SWNTs). The nanotubes are embedded with biological ligands (e.g., antibodies). The electrical resistance of a semiconducting SWNT is found to dramatically increase upon the actuation by a specific antigen. Measurement of the change in resistance correlates with the concentration of the specific antigen and thus provides for quantitative determination and diagnostics of biological samples. The simple printing fabrication of electrical percolation biological semiconductors (EPBSC) can facilitate assembly of numerous types of gates (e.g., antibodies, DNA, etc.) and print many of such gates on the same chip for the creation of biological CPUs for various biomedical applications, including direct biodetection and regulation of implantable biomedical devices. CRADA Opportunity: The National Cancer Institute, Cancer Diagnostic Program, and the Food and Drug Administration, the Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Electrical Percolation Biological Semiconductors for biodetection. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Mobilizing the Body to Fight Cancer: T Cell Receptors Specific for the Tumor Antigen Survivin

Fri, 15 May 2009 19:00:00 GMT

A major drawback of current chemotherapy-based cancer treatments is the harsh side-effects associated with many cancer drugs. Thus, there is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity. Immunotherapy is a promising new cancer therapeutic approach that directs an individual's innate and adaptive immune system to fight against specific diseases, including cancer.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins.

Scientists at the National Institutes of Health (NIH) have developed genetically-modified T cells, which possess TCRs that specifically recognize human survivin, a tumor antigen expressed in many adult and pediatric cancers that is absent from most normal tissues. Non-human T cells that recognized human survivin peptides with high affinity in the context of human leukocyte antigen (HLA) alleles were identified. Then, using recombinant DNA technology, the survivin-specific TCRs from the non-human T cells were fused to human TCR backbones and expressed in human T cells. The resulting survivin-specific human T cells could prove to be powerful new immunotherapeutic tools for attacking survivin-expressing tumors after infusion into patients. CRADA Opportunity: The National Cancer Institute Pediatric Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize genetically engineered lymphocytes with specificity for human survivin. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Salcut-NH2: A Novel Target for Development of Anti-Tumorigenic, Anti-Angiogenic Therapeutics and Diagnostics

Tue, 05 May 2009 23:00:00 GMT

Salcut-NH2, a novel amidated peptide derived from the Apelin proprotein, is shown to induce the proliferation of cells. Uncontrolled cell proliferation is the salient feature of cancer. Thus, therapeutics that stop this aberrant cell division are very desirable. Salcut-NH2 can be the basis for developing novel inhibitors of cancer growth such as modified peptide antagonists like salcut-glycine (salcut-Gly). Alternately, salcut-NH2 could be the target of antibody therapies that block its activity. In some instances, such as wound healing, inducing cell proliferation would be advantageous. It also has been demonstrated that salcut-NH2 induces angiogenesis so it may also have application as a topically administered therapeutic for speeding the healing of skin wounds. Finally, increasing levels of salcut-NH2 in body fluids may be reflective of disease progression. A diagnostic kit for salcut-NH2 could potentially be developed for the prognosis of a variety of diseases associated with aberrant cell proliferation or angiogenesis. CRADA Opportunity: The National Cancer Institute Angiogenesis Core Facility is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize 1) Identification of new biological functions for Salcut-NH2 or 2) Development of compounds that suppress or augment Salcut-NH2 bioactivity. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Immunogenic West Nile Virus-Like Particles

Wed, 06 May 2009 03:00:00 GMT

Currently, no specific vaccine or therapy for West Nile Virus (WNV) is available for human use; a killed-virus vaccine and booster is in use for horses (efficacy not yet reported). Virus-like particles (VLPs) are an exciting new strategy, as it combines the safety of killed-virus and DNA-based vaccines with the potential for immunogenicity of live-attenuated virus. VLPs have been used in approved vaccine for humans, including human papilloma virus (HPV). Generating VLPs for West Nile Virus, however, has proven difficult.

The inventors have successfully generated West Nile VLPs in insect cells by using recombinant baculoviruses expressing the WNV structural proteins prME or CprME. Mice immunized with purified West Nile VLPs developed antibodies specific to WNV with potent neutralizing activities; moreover, the mice showed no morbidity or mortality after a subsequent challenge with live WNV and showed no evidence of viremia or viral RNA in the spleen or brain.

The patent application covers applications ranging from pharmaceutical/vaccine preparations for WNV-LPs to methods for making and using them. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Liver Diseases Branch, is seeking parties interested in collaborative research directed toward molecular strategies for vaccine and antiviral development, and animal models of viral hepatitis C. For more information, please contact Dr. T. Jake Liang at 301-496-1721, jliang@nih.gov, or Ms. Patricia Lake at 301-594-6762, lakep@mail.nih.gov.

Method of Detecting and Quantifying Contaminants in Heparin Preparations

Tue, 05 May 2009 07:00:00 GMT

Heparin is a naturally occurring acidic carbohydrate produced commercially from extracts of animal tissues (such as bovine lung or porcine intestine) and is used in the treatment of a wide range of diseases in addition to their classic anticoagulant activity. Heparin is also used to coat many medical devices, such as catheters, syringes, stents and filters. Recently, certain lots of heparin were associated with serious side effects and adverse events. Recalls were issued in multiple countries and it became evident that there was an extensive problem with heparin manufacture.

Traditional tests may not be able to determine the presence of contaminant(s) without lyophilizing and concentrating each sample and may not be suitable for testing finished medical devices. Therefore, there is a demonstrated need to develop other assay methods for detecting contaminating oversulfated compounds of any source in heparin and heparin derived products.

This technology relates to methods for detecting and/or quantifying oversulfated glycosaminoglycans based on inhibition of nucleic acid polymerases and resistance to enzymatic degradation. It also relates to the use of these methods to screen and quantify pharmaceutical preparations such as heparin preparations for oversulfated contaminants. CRADA Opportunity: The FDA, Division of Therapeutic Proteins, Laboratory of Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this high throughput screening test for oversulfated glycosamineglycan contaminants in heparin. Please contact Daniela Verthelyi at daniela.verthelyi@fda.hhs.gov or Alice Welch at alice.welch@fda.hhs.gov for more information.

Novel Means of Regulation of Gene Expression: Modular and Artificial Splicing Factors

Tue, 05 May 2009 11:00:00 GMT

This discovery provides a new therapeutic approach for treatment of diseases caused by altered gene regulation resulting from defective alternative splicing of genes. This technology offers the following advantages over currently available methods for regulating splicing: a) delivery can be through standard gene therapy methods, such as viral vectors, b) site of delivery of the artificial splicing factors can be controlled, which enables targeted expression and limited side effects, and c) the artificial splicing factors described here can be readily adapted to a variety of splicing effector modules. This invention provides proteins that combine an RNA recognition module that can specifically target an endogenous pre-mRNA with splicing effector modules that alter splicing to favor a particular isoform of a mature mRNA.

The artificial splicing factors disclosed here can be used to treat conditions requiring directed alternative splicing. For example, the artificial splicing factors described here can be used in combination with other anti-tumor drugs as a cancer treatment. Other examples where this technology may find use include diabetes (insulin receptor), psoriasis (fibronectin), polycystic kidney disease (PKD2), and prostate cancer (fibroblast growth factor receptor 2). CRADA Opportunity: The NIEHS Division of Intramural Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Modular and Artificial Splicing Factors. Please contact Elizabeth M. Denholm, Ph.D. at 919-541-0981 or denholme@niehs.nih.gov or Traci Hall, Ph.D. at hall4@niehs.nih.gov for more information.

Mast Cells Defective in the Syk Protein Tyrosine Kinase

Tue, 05 May 2009 15:00:00 GMT

NIH investigators, through screening for variants of RBL-2H3 cells, have identified and developed TB1A2 mast cells that are defective in the expression of the Syk protein tyrosine kinase. These cells had no detectable Syk protein by immunoblotting or in vitro kinase reaction, and no detectable Syk mRNA by Northern hybridization. These TB1A2 cells failed to secrete or generate cytokines after high affinity receptor for immunoglobulin E (Fc epsilon RI) stimulation. In these Syk-deficient TB1A2 cells, aggregation of these receptors did not induce histamine release and there was no detectable increase in total cellular protein tyrosine phosphorylation. However, stimulation of these cells with the calcium ionophore did induce degranulation. These cells provide a useful experimental model to study the role of Syk tyrosine kinase in signal transduction pathways in immune cells. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Oral Infection and Immunity Branch, Receptors and Signal Transduction Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

Small Molecule Activators of Human Pyruvate Kinase for Treatment of Cancer and Enzyme-Deficient Hemolytic Anemia

Tue, 05 May 2009 19:00:00 GMT

NIH investigators have discovered a series of small compounds with the potential to treat a variety of cancers as well as hemolytic anemia. Contrary to most cancer medications, these molecules can be non-toxic to normal cells because they target a protein specific to the metabolic pathways in tumors, thus representing a significant clinical advantage over less-specific chemotherapeutics.

The invention described here is a series of small molecules that activate pyruvate kinase (PK) isoform M2. PK-M2 is a critical metabolic enzyme that is affected in all forms of cancer. Inactivation of PK-M2 leads to a buildup of metabolic intermediates inside the cell. Tumor cells require a buildup of metabolic intermediates in order to undergo rapid cell growth and proliferation. Hence, activation of PK-M2 in tumor cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation or destroy the tumor cells. Further, while in normal adult cells only PK isoforms R, L, or M1 are active, in all tumors only PK-M2 is active. Therefore, PK-M2 activation would affect only tumor cells, and small-molecule PK-M2 activators are not expected to be toxic to healthy cells.

In addition, in patients with PK-R deficiency the buildup of metabolic intermediates in red blood cells ultimately leads to the loss of water from the cells and cell death. Small-molecule induced activation of PK-R in PK-deficient red blood cells may enhance vitality of these cells and decrease or eliminate enzyme-deficient hemolytic anemia in a patient. CRADA Opportunity: The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/199,763. Please contact Dr. Craig J. Thomas via e-mail (craigt@nhgri.nih.gov) for more information.

Magnetic Resonance Specimen Evaluation Using Multiple Pulse Field Gradient Sequences

Mon, 04 May 2009 23:00:00 GMT

The invention proposes and claims an MRI-method that is based on the measurement and acquisition of multiple pulsed field gradient (m-PFG) rather than the previously used single-pulsed field gradient (s-PFG) MRI sequences. In particular, double PFG (d-PFG) sequences offer higher sensitivity and greater robustness, as it is more sensitive to the effect of “restriction”, i.e., to water trapped within the axon’s intracellular space, and thus to the diameter of the axons. It renders the MR sequence more sensitive to “pore size” and “pore shape” and thus makes the measurement of the ADD more sensitive and accurate. Moreover, measurements using the multiple-PFG sequence can be performed readily at “low b” or “low q”, making it biologically relevant and clinically feasible.

A detailed announcement describing the licensing opportunity for this and related technologies referenced below was published in the Federal Register on Tuesday, April 14, 2009 (74 FR 17199-17201). CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Tissue Biophysics and Biomimetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel MRI methods to probe tissue structure and organization, particularly for neuroimaging applications. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information.

Non-Invasive in vivo MRI Axon Diameter Measurement Methods

Tue, 05 May 2009 03:00:00 GMT

This invention describes an improvement and continuation of the CHARMED MRI framework described above, extending this technology to measure the axon diameter distribution (ADD) of nerve bundles (fascicles) in the central and peripheral nervous systems.

The invention essentially consists of a non-obvious combination of CHARMED MRI and an improvement of an NMR method, originally developed for particle sizing in porous media applications, which was extended and enhanced to provide a direct measurement of the ADD within nerve fascicles in the brain, spine or other parts of the peripheral nervous system on a voxel-by-voxel basis. Additionally this approach can be extended to measure the fiber orientation distribution of axons within each voxel of an imaging volume and particularly the myelin content within each voxel.

The significance of this invention is that it represents a way to provide a non-invasive, painless, in vivo measurement of microanatomical (histological) features of nerves (and possibly muscles) that are critically important in medicine and the neurosciences and previously were only available using invasive histological means requiring biopsy. The ADD is altered in abnormal development (possibly even in autism), in degenerative processes (e.g., aging, alcoholism, Alzheimer's disease) and diseases such as ALS (Lou Gehrig's disease). The ADD is a critically important parameter of a nerve bundle from a neuroscience perspective because axon diameter determines the conduction velocity of action potentials, and thus the arrival time and latency of nerve impulses traveling along them. The orientation or directional distribution of axons is important in Tractography applications to help determine how different cortical regions of the brain are connected to each other via white matter pathways. Myelin is dynamically regulated in vivo and affects the electrical insulating property of axons, and thus the conduction velocity of nerves. Myelin content is a critically important parameter in MS and a large number of dysmyelinating and demyelinating diseases as well as in normal and abnormal development.

A detailed announcement describing the licensing opportunity for this and related technologies referenced below was published in the Federal Register on Tuesday, April 14, 2009 (74 FR 17199-17201). CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Tissue Biophysics and Biomimetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel MRI methods to probe tissue structure and organization, particularly for neuroimaging applications. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information.

Identification of Subjects Likely to Benefit from Copper Treatment

Mon, 04 May 2009 07:00:00 GMT

Menkes disease is an infantile onset X-linked recessive neurodegenerative disorder caused by deficiency or dysfunction of a copper-transporting ATPase, ATP7A. The clinical and pathologic features of this condition reflect decreased activities of enzymes that require copper as a cofactor, including dopamine-beta-hydrolase, cytochrome c oxidase and lysyl oxidase. Recent studies indicate that ATP7A normally responds to N-methyl-D-aspartate receptor activation in the brain, and an impaired response probably contributes to the neuropathology of Menkes disease. Affected infants appear healthy at birth and develop normally for 6 to 8 weeks. Subsequently, hypotonia, seizures and failure to thrive occur and death by 3 years of age is typical. Occipital horn syndrome (OHS) is also caused by mutations in the copper transporting ATPase ATP7A, although its symptoms are milder than Menkes syndrome, including occipital horns and lax skin and joints.

Treatment with daily copper injections may improve the outcome in Menkes disease if commenced within days after birth; however, newborn screening for this disorder is not available and early detection is difficult because clinical abnormalities in affected newborns are absent or subtle. Moreover, the usual biochemical markers (low serum copper and ceruloplasmin) are unreliable predictors in the neonatal period, since levels in healthy newborns are low and overlap with those in infants with Menkes disease. Although molecular diagnosis is available, its use is complicated by the diversity of mutation types and the large size of ATP7A (about 140kb). Thus, there is a need for improved methods for early detection of infants with Menkes disease or OHS in order to improve outcomes.

This technology relates to methods of identifying individuals who may benefit from treatment with copper, particularly those having Menkes disease or Occipital Horn Syndrome. CRADA Opportunity: The National Institute of Child Health and Human Development, Division of Intramural Research, Molecular Medicine Program, Unit on Pediatric Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize population-based newborn screening for Menkes disease and related disorders of copper transport in order to identify subjects likely to benefit from copper injections and other treatments. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information.

An Imaging Radiotracer for the Noninvasive Detection of HER2-positive Tumors

Mon, 04 May 2009 11:00:00 GMT

Investigators at the NIH have developed a novel imaging radiotracer composed of an Affibody® molecule uniquely labeled with ¹⁸F for noninvasively locating and measuring the expression of HER2 breast cancer biomarker in tumors anywhere in the body. The over expression of HER2 in cells is a diagnostic marker for a particularly aggressive form of breast cancer. Currently, localized biopsies are needed to diagnose HER2-positive breast cancer. Noninvasive detection of HER2-positive cells in whole body will help to identify patients that can benefit from HER2-targeted therapies such as the monoclonal antibody trastuzumab. This imaging compound will also be useful for monitoring the tumor response to HER2-targeted therapies. The use of an Affibody® molecule is advantageous because it is a recombinant protein of relatively small size (more than 20 times smaller than antibodies), readily producible and has a high binding affinity for HER2. This allows the imaging compound to permeate the body easily and bind to the HER2-positive cells selectively. Conjugating the Affibody® molecule to the positron-emitting radionuclide ¹⁸F enables noninvasive imaging using positron emission tomography (PET). The utility of this targeted radiotracer for detecting HER2-positive tumors has already been validated in animals. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Affibody® molecules for diagnosis and molecular therapy of HER1- or HER2-positive tumors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Peptides for Treating Mesothelin- and/or CA125-Expressing Cancers

Mon, 04 May 2009 15:00:00 GMT

Mesothelin is a cell surface glycoprotein that is highly expressed in many cancers, including malignant mesothelioma and ovarian cancer. Mesothelin interacts with another cell surface protein that is also highly expressed on some cancer cells: CA125 (MUC16). Evidence indicates that this interaction mediates cell adhesion during tumor implantation and metastasis. This suggested that the disruption of the mesothelin-CA125 interaction may prevent the growth and spreading of tumors.

NIH inventors have generated specific peptides, based on the CA125 binding domain of mesothelin, that block the interaction between mesothelin and CA125. Significantly, blocking the interaction disrupted cell adhesion in cancer cells expressing both mesothelin and CA125. Antibodies that recognize the specific mesothelin peptides were also capable of disrupting the mesothelin-CA125 interaction. The peptides bound CA125 on cancer cells. As a result, these peptides are excellent candidates for a new cancer therapeutic. CRADA Opportunity: The National Cancer Institute, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize peptides for treating mesothelin- and/or CA125-expressing cancers. Please contact Mitchell Ho at 301-451-8727 and/or homi@mail.nih.gov for more information.

Treating Cancer through Immunotherapy with Herceptin-Based Receptors Specific for ErbB2 (Her2/Neu)

Mon, 04 May 2009 19:00:00 GMT

There is an urgent need to develop new therapeutic strategies for patients with cancer that combine fewer side-effects and more specific anti-tumor activity. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual’s innate and adaptive immune system to fight against specific diseases, including cancer.

Chimeric antigen receptors (CARs) are hybrid proteins consisting of the portion of an antibody that recognizes a tumor-associated antigen (TAA) fused to protein domains that signal to activate the CAR-expressing cell. Human cells that express CARs, most notably T cells, can recognize specific tumor antigens with high reactivity to mediate an immune response that promotes tumor killing in targeted cancer cells.

Scientists at the National Institutes of Health (NIH) have developed CARs with high affinity for the ErbB2 (also known as Her2/Neu) antigen, which is overexpressed on a variety of cancer cells, including lung, breast, colorectal, ovary, prostate, and head and neck squamous cell cancer. These ErbB2-specific CARs are herceptin-based receptors composed of the part of a humanized herceptin antibody that recognizes ErbB2 and a portion of the T cell receptor (TCR)-related protein, CD3. The herceptin-CAR framework was selected since the herceptin monoclonal antibody has been proven to be an effective treatment for breast cancer. These ErbB2-specific CARs expressed in the context of T cells could prove to be powerful new immunotherapeutic tools for attacking ErbB2+ tumors after their infusion into patients. CRADA Opportunity: Dr. Steven A. Rosenberg of the NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutic T cell receptor technologies. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Live-Attenuated West Nile Virus Vaccines with Improved Immune Responses

Mon, 04 May 2009 23:00:00 GMT

West Nile virus (WNV), the etiologic agent of West Nile virus fever and encephalitis, is an emerging human and veterinary pathogen in North America. WNV also periodically poses a serious threat to public health in Africa, Australia, Europe, the Middle East, and Asia. There is no vaccine available. WNV strains are phylogenetically grouped into two distinct lineages based primarily on differences within the envelope (Env) protein gene segment. The highly virulent strains recently emergent on the North American continent are of lineage I. Lineage I viruses are primarily also isolated in the Middle East, Europe, and parts of Africa. Lineage II viruses are mostly isolated in Africa. Both lineages include highly neurovirulent as well as relatively attenuated strains of WNV.

WN vaccine viruses developed by others are chimeric live attenuated WN vaccine viruses. The genomes of these viruses encode the C and NS proteins of dengue or yellow fever virus, respectively, along with the WNV prM and Env proteins, which are the major targets of the humoral immune response to flaviviruses. These chimeric live attenuated WN vaccines have been successful in animal testing and some are currently in clinical trials. However, these vaccines have two potential disadvantages due to their heterogeneous genetic composition: (i) animal host range may be different from that of wild-type WNV, rendering the vaccines less than optimal for immunization of some at-risk species and (ii) the elicited immune response may be suboptimal in duration or quality, due to the absence from these vaccines of homologous WN NS proteins.

FDA’s technology that is available for licensing comprises live attenuated West Nile viruses that are not chimeric, but instead have one or more mutations in the 3' terminal stem loop secondary structure, resulting in decreased neurovirulence. The related patent application also claims methods of making the viruses claimed in the application and methods for using these viruses to prevent or treat WN infection. More specifically, the inventors modified infectious WN DNA such that all or segments of the wild-type WN 3' stem loop nucleotide sequence was replaced with analogous dengue virus serotype 2 3' stem loop sequences. The inventors also created a number of point mutations in the nucleotide sequence of the WN 3' stem loop sequence. CRADA Opportunity: The FDA Office of Vaccines Research & Review is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize West Nile Virus vaccines. Please contact Alice Y. Welch, Ph.D., at 301-827-0359 or Alice.Welch@fda.hhs.gov for more information.

Anti-Cancer Oligodeoxynucleotides

Tue, 05 May 2009 03:00:00 GMT

A majority of human cancers originate from epithelial tissue. A common cancer of epithelial cell origin is non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with more than seven hundred thousand (700,000) new cases diagnosed each year in the United States alone. BCC is rarely life-threatening because it is slow growing and is mostly localized. Unlike BCC, SCC metastasizes at a rate of two (2) to six (6) percent over several years after the initial diagnosis. A highly malignant form invades and destroys tissue, and then metastasizes, initially to a regional lymph node before more distant organs such as the lungs or brain are affected. SCC is commonly encountered in a number of epithelial tissues, including the oral cavity, esophagus, larynx, bronchi, intestines, colon, genital tract, and skin.

This application relates to suppressive CpG oligodeoxynucleotides (ODNs). This application claims suppressive ODN compositions and their use to prevent or delay the formation of a tumor, reducing the risk of developing a tumor, treating a tumor, preventing conversion of a benign to a malignant lesion, or preventing metastasis. Topical application of the ODNs of this invention in preclinical studies resulted in significantly fewer animals developing papillomas and fewer papillomas/animal. The invention also relates to use of suppressive ODNs to prevent/delay cancer when administered systemically as well as locally. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Insect Salivary Proteins as Potent Adjuvants for Enhancing Immune Responses

Mon, 04 May 2009 07:00:00 GMT

This invention relates to the discovery that specific sand fly salivary proteins have marked effects on the outcome of Leishmania infection. These proteins have the ability to stimulate strong Th1 and Th2 responses. The Th1 responses with one protein, PpSP15, result in immune protection while the Th2 responses to another protein, PpSP44, exacerbate infection. The protective protein enhanced a specific immune response to the infection, suggesting that it acts as an adjuvant to alter the environment and presentation of the parasite antigens.

These immunogenic salivary proteins, capable of driving Th1 or Th2 responses, can be used as adjuvants in vaccine development for a broad spectrum of diseases that require different immune responses. They may therefore be used to enhance immune responses to pathogens other than Leishmania parasites. They are also very potent in their effect, and small doses are sufficient to elicit a strong immune response. This potency can reduce the need to use chemical adjuvants, which often require large mounts of material and can have deleterious side effects. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Insect Salivary Proteins as potent immune response adjuvants. Please contact Charles Rainwater at crainwater@niaid.nih.gov or 301.496.2644 for more information.

Substituted Triazine and Purine Compounds for the Treatment of Chagas Disease and African Trypanosomiasis

Mon, 04 May 2009 11:00:00 GMT

Parasitic protozoa are responsible for a wide variety of infections in both humans and animals. Trypanosomiasis poses health risks to millions of people across multiple countries in Africa and North and South America. Visitors to these regions, such as business travelers and tourists, are also at risk for contracting parasitic diseases. There are two types of African trypanosomiasis, also known as sleeping sickness. One type is caused by the parasite Trypanosoma brucei gambiense, and the other is caused by the parasite Trypanosoma brucei rhodesiensi. If left untreated, African sleeping sickness results in death. Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects millions of people in Mexico and South and Central America. Untreated, Chagas disease causes decreased life expectancy and can also result in death.

The subject invention covers novel triazine and purine compounds that are inhibitors of key proteases (cruzain and Rhodesian) of the parasites Trypanosoma brucei rhodesiensi and Trypanosoma cruzi, respectively. CRADA Opportunity: The NIH Chemical Genomics Center (NCGC) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in the patent application. Please contact Dr. Craig J. Thomas (craigt@nhgri.nih.gov) or Claire Driscoll (cdriscol@mail.nih.gov), Director of the NHGRI Technology Transfer Office, for more information.

Small-Molecule TSH Receptor Modulators for Diagnosis and Treatment of Thyroid Disease and Cancer

Mon, 04 May 2009 15:00:00 GMT

NIH investigators have discovered a series of low molecular weight thyroid-stimulating hormone (TSH) receptor modulators for use in evaluation and treatment of thyroid diseases, including thyroid cancer, hypothyroidism, and hyperthyroidism. Certain compounds encompassed by this technology are more potent and/or more specific TSH receptor activators than currently-available compounds; also, as small molecules, these compounds are orally available and are expected to be less costly and more straightforward to produce than recombinant protein counterparts currently on the market.

According to the National Cancer Institute, over 37,000 new cases of thyroid cancer were diagnosed in the United States in 2008, and over 1,500 people died of this disease. These numbers reflect a progressive increase in the incidence of thyroid cancer over the last several years. Because most cases of thyroid cancer are diagnosed in patients between the ages of 20 and 54, these patients will undergo decades of follow-up monitoring after cancer treatment. For the last decade, recombinant TSH protein has been used in this follow-up to increase detection sensitivity for recurrent or metastatic thyroid cancer, and to eliminate side effects associated with withdrawal of hormone replacement therapy. A small-molecule TSH receptor agonist encompassed by this technology would have utility similar to recombinant TSH, but would have several distinct advantages. For example, as a small molecule, rather than a recombinant protein, such a compound would be orally available, and would be less difficult and expensive to produce. These compounds are also more potent and/or specific for the TSH receptor than other known small-molecule TSH receptor agonists. In addition to use in thyroid cancer screening, these compounds may also be useful for adjunctive treatment (with radioactive iodide) of thyroid cancer, and certain forms of hypothyroidism.

Hyperthyroidism, or an overactive thyroid gland, affects about 1% of people in the United States and is often caused by autoimmune over-stimulation of the thyroid gland (Graves’ disease), or by thyroid tumors. Drugs currently used for treatment of hyperthyroidism inhibit synthesis of thyroid hormones; the TSH receptor antagonist compounds encompassed by this technology have the advantage of directly inhibiting activity of the TSH receptor, rather than inhibiting thyroid hormone synthesis. CRADA Opportunity: The NIDDK Clinical Endocrinology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize small molecule TSH receptor modulators. Please contact Marguerite J. Miller at 301-496-9003 or millermarg@mail.nih.gov for more information.

Modulating Expression of the Metastasis Suppressor MxA

Mon, 04 May 2009 19:00:00 GMT

The invention discloses compounds that could be used to inhibit metastases. The compounds of the current invention were discovered by high-throughput screening of a novel cell line engineered with a MxA reporter. The compounds could be used to treat metastatic cancers including prostate and melanomas by increasing MxA expression.

MxA expression reduces cell motility and metastases in a mouse model. Cells expressing MxA produced smaller tumors in engrafted mice compared to controls. When injected into mouse spleens, cells expressing MxA showed a significantly delayed metastasis, and the mice survived significantly longer than controls. Expression of MxA reduced cellular motility of prostate cancer cell lines in vitro and reduced cellular motility and invasiveness of the highly metastatic melanoma cell line LOX. In addition to the use of the instant MxA compounds as antimetastatic agents, MxA is a known effective anti-viral agent and the MxA-inducing compounds could be used to treat infections sensitive to the antiviral activity of MxA, which potentially include myxovirus-associated disease. CRADA Opportunity: The National Cancer Institute, Medical Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

On-Demand In Vitro Assembly of Protein Microarrays

Mon, 04 May 2009 23:00:00 GMT

Protein microarrays are becoming an indispensable biomedical tool to facilitate rapid high-throughput detection of protein-protein, protein-drug and protein-DNA interactions for large groups of proteins. The novel Protein Microarray of this invention is essentially a DNA microarray that becomes a protein microarray on demand and provides an efficient systematic approach to the study of protein interactions and drug target identification and validation, thereby speeding up the discovery process. The technology allows a large number of proteins to be synthesized and immobilized at their individual site of expression on an ordered array without the need for protein purification. As a result, proteins are ready for subsequent use in binding studies and other analysis.

The Protein Microarray is based on high affinity and high specificity of the protein-nucleic acid interaction of the Tus protein and the Ter site of E. coli. The DNA templates are arrayed on the microarray to perform dual function: (1) synthesizing the protein in situ (cell-free protein synthesis) in the array and (2) at the same time capturing the protein it synthesizes by DNA-protein interaction. This method utilizes an expression vector containing a DNA sequence which serves a dual purpose: (a) encoding proteins of interest fused to the Tus protein for in vitro synthesis of the protein and (b) encoding the Ter sequence, which captures the fusion protein through the high affinity interaction with the Tus protein. CRADA Opportunity: The National Cancer Institute Protein Expression Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize in vitro assembly of protein microarrays. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Transgenic Mice in which the Gene for MCP-1 is Deleted

Tue, 05 May 2009 03:00:00 GMT

Dr. Yoshimura has developed a transgenic mouse which does not express the chemokine MCP-1 due to a deletion of the gene for MCP-1. MCP-1 is a CC chemokine which is responsible for recruiting monocytes into sites of inflammation and cancer. Using a thioglycollate challenge as a measure of the impact of the deletion of MCP-1, MCP-1 deficient mice exhibit a 60% reduction in the number of monocytes/macrophages at 96 hours compared to wild type mice. Unlike previously generated MCP-1 deficient mice in which the expression of the neighboring gene for MCP-3 is down-regulated (our own data), the expression of MCP-3 is up-regulated in this mouse model. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents useful to treat patients with inflammation or cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Diffusion Tensor and q-Space MRI Specimen Characterization

Mon, 04 May 2009 07:00:00 GMT

Diffusion Tensor MRI (DTI or DT-MRI) – a technique described in U.S. Patent 5,539,310 and implemented by all major commercial MRI systems – provides information primarily about how water diffuses in the extracellular compartment of tissues, where water mobility is hindered (i.e., where water diffuses freely but encounters barriers from which it is reflected). However, DTI does not provide a complete characterization of diffusion in the intracellular compartment of some cells, particularly myelinated axons, where water mobility is restricted by impermeable membranes (i.e., where water is trapped but otherwise free to diffuse within the cell).

The subject invention provides a new modeling framework that self-consistently describes 3-D anisotropic diffusion within a hindered extracellular compartment and within a restricted intra-axonal compartment. It results in an improved characterization and measurement tissue and cell microstructure in neuronal tissue, which promises to advance diagnosis of neurological conditions (e.g., Stroke, MS, Alzheimer’s disease), possibly cognitive and behavioral disorders (e.g., schizophrenia), as well as our ability to follow normal development and aging processes.

More specifically, this new in vivo diffusion MRI method, especially suited for the characterization of brain white matter, marries q-space and DTI concepts: Diffusion within axons is modeled as hindered diffusion parallel to the axis of the axon, and restricted diffusion perpendicular to the axis. Diffusion exterior to axons is modeled as hindered diffusion with differing diffusivities parallel and perpendicular to the nerves’ axis. To practice this method, diffusion weighted (DW) MRI data are acquired from specimens at different q-values (with different diffusion gradient magnitudes and directions). Parameters associated with tissue microstructure, such as the intra and extra-axonal principal diffusivities and their corresponding principal directions, and the volume fractions of intra and extra-axonal space are then estimated from these data. Improved angular resolution of fiber tract orientation can be obtained for tractography studies and more microstructural information can be gleaned for both diagnostic and therapeutic purposes than from conventional DTI. This technology has been named CHARMED (Composite Hindered and Restricted Model of Diffusion).

A detailed announcement describing the licensing opportunity for this and related technologies referenced below was published in the Federal Register on Tuesday, April 14, 2009 (74 FR 17199-17201). CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Tissue Biophysics and Biomimetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel MRI methods to probe tissue structure and organization, particularly for neuroimaging applications. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information.

Improved Expression Vectors for Mammalian Use

Mon, 04 May 2009 11:00:00 GMT

This technology relates to improving levels of gene expression using a combination of a constitutive RNA transport element (CTE) with a mutant form of another RNA transport element (RTE). The combination of these elements results in a synergistic effect on stability of mRNA transcripts, which in turn leads to increased expression levels. Using HIV-1 gag as reporter mRNA, one mutated RTE in combination with a CTE was found to improve expression of unstable mRNA by about 500-fold. Similarly this combination of elements led to synergistically elevated levels of HIV-1 Env expression. The function of CTEs and RTEs is conserved in mammalian cells, so this technology is a simple and useful way of obtaining high levels of expression of otherwise poorly expressed genes and can be used in a number of applications such as but not limited to improvements of gene therapy vectors, expression vectors for mammalian cells. CRADA Opportunity: The National Cancer Institute Vaccine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Neuronal Decoding Algorithm for Prosthetic Limbs

Mon, 04 May 2009 15:00:00 GMT

The invention is a new algorithm for decoding neuronal responses based on the discovery that neuronal spike trains can be described using order statistics. The device has applications in the direct control of prosthetic limbs by neuronal signals originating from electrodes placed in the brain. The method allows for decoding neuronal responses by monitoring sequences of potentials from neurons while specific motor tasks are carried out. The sequences are then characterized using the innovative technique of applying order statistics to the spike train, such that subsequent action potentials representing unidentified motor tasks can be decoded to determine the unknown task. The invention is of substantial importance because it appears to have achieved a closed form interpretation of neuronal responses upon which a motor prosthetic device might be based. CRADA Opportunity: The National Institute of Mental Health, Laboratory of Neuropsychology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize decoding algorithm for neuronal responses. Please contact Suzanne Winfield at winfiels@mail.nih.gov or 301-402-4324 for more information.

Mouse Monoclonal Antibodies to Human Tristetraprolin (TTP)

Wed, 25 Mar 2009 19:00:00 GMT

TTP has been implicated in autoimmune and inflammatory diseases through its role as a regulator of the transcripts encoding several pro-inflammatory cytokines, including tumor necrosis factor alpha. However, it has been difficult to study endogenous TTP in man and other animals because it is expressed at very low levels in most cells and tissues, and because of the lack of mouse monoclonal antibodies directed at the human protein.

Scientists at the NIH have developed three mouse monoclonal antibodies (TTP-16, TTP-214 and TTP-409) that react to different regions of the human TTP to allow for the identification and localization of the TTP protein by standard protocols. Although validation has only been conducted at the level of western blotting to date, they do not appear to cross-react with other human members of the TTP protein family. CRADA Opportunity: The NIEHS, Polypeptide Hormone Action Group, of the Laboratory of Signal Transduction, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antibodies to human TTP. Please contact Dr. Elizabeth M. Denholm in the Office of Technology Transfer (denholme@niehs.nih.gov), or Dr. Perry Blackshear (black009@niehs.nih.gov) for more information.

Cell Based Immunotherapy

Wed, 25 Mar 2009 23:00:00 GMT

The invention hereby offered for licensing is in the field of Immunotherapy and more specifically in therapy of autoimmune diseases such as Type I diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosis and immune mediated allergies such as asthma as well as in transplantation-related disorders, such as graft acceptance and graft-versus-host-disease (GVHD).

While the role of FOXP3⁺ regulatory T cells (Tregs) in the maintenance of self-tolerance and immune homeostasis has been established and thus their use in adoptive immunotherapy has been contemplated, there is still no good way to purify and expand these cells in an efficient and reproducible manner ex vivo for use in human therapy. The subject invention provides a method that allows such purification for use in expansion cultures to generate sufficient numbers of cells and purity for cell-base immunotherapy. The method is based on the finding that Tregs selectively express Latency Associated Peptide (LAP) and CD121b (IL-1 Receptor Type 2) and on the ability to selectively separate these cells from other immune cells that are potentially hazardous, through the use of magnetic particles which specifically bind to either one of these two surface molecules and selectively separate those cells from the non-Tregs. CRADA Opportunity: The NIAID/NIH Laboratory of Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of CD121b or LAP to produce a Treg product for cell-based immunotherapy. Please contact Nicole Mahoney at 301-435-9017 for more information.

Radiotracers for Imaging P-glycoprotein Transporter Function

Wed, 25 Mar 2009 03:00:00 GMT

This invention offers technology to help treat certain brain diseases, such as Alzheimer's disease and Parkinson's, and may lead to more effective and personalized treatments. P-glycoprotein transporter (P-gp) acts as a pump at the blood-brain barrier to exclude a wide range of xenobiotics (e.g., toxins, drugs, etc.) from the brain and is also expressed in a tumor in response to exposure to established/prospective chemotherapeutics (a phenomenon known as multidrug resistance; MDR). The instant invention relates to compounds that are avid substrates for P-gp, and their preparation and use as radiotracers for imaging P-gp function in vitro and in vivo. CRADA Opportunity: The National Institute of Mental Health Molecular Imaging Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize radiotracers for imaging P-gp function. Please contact Victor Pike at pikev@mail.nih.gov for more information.

Lasonolide Compounds as Reagents for Inducing Premature Chromosome Condensation and Methods of Treating Cancer

Mon, 23 Mar 2009 07:00:00 GMT

Lasonolide A is a natural product initially isolated from an extract of the shallow water Caribbean marine sponge. The chemical structure of lasonolide A was identified in 2002, and it was chemically synthesized in 2007. The current invention discloses the discovery that lasonolide A may be used as a new reagent for inducing premature chromosome condensation in non-dividing cells; and a novel anti-proliferative and anti-metastatic agent for cancer treatment. Currently, it is difficult to analyze the cytogenetic composition of the genome of non-dividing cells because the chromosomes are loosely distributed in the nucleus, lasonolide A may be useful for performing cytogenetic studies in cells by inducing premature chromosome condensation without inducing mitosis. In addition, the invention also reveals that lasonolide A inhibits cancer cell motility. As such, lasonolide A may be used as an anti-cancer agent by itself or in combination with other anti-cancer agents such as inhibitors of topoisomerases. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Pharmacology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Lasonolide Compounds as Reagents for Inducing Premature Chromosome Condensation and Methods of Treating Cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Gene Signature for Predicting Solid Tumors Patient Prognosis

Mon, 23 Mar 2009 11:00:00 GMT

A progressive sequence of somatic mutations and epigenetic changes of oncogenes or tumor suppressor genes are believed to cause tumor development. However, high genomic instability in tumors causes the accumulation of genomic aberrations that do not contribute to tumor progression. Therefore it is important to distinguish between ‘driver’ mutations which are functionally important and ‘passenger’ mutations which do not provide a selective advantage to the tumor cells.

The current invention describes a driver gene signature for predicting survival in patients with solid malignancies including hepatocellular carcinoma (HCC) and breast cancer. The gene signature includes ten cancer-associated genes, and the NIH researchers further discovered that a decrease in DNA copy number or mRNA expression of some genes is associated with poor prognosis in HCC tumors and breast cancer, while a decrease in DNA copy number or mRNA expression of a few other genes is associated with good prognosis. They have also demonstrated that at least four of these cancer-associated genes are functional tumor suppressor genes. Thus, these genes may be potential molecular targets of HCC and breast cancer.

Available for licensing is a method of predicting the prognosis of a patient diagnosed with HCC or breast cancer by detecting expression of one or more cancer-associated genes, and a method of identifying an agent for use in treating HCC. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Human Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this Gene Signature for Predicting Hepatocellular Carcinoma Patient Prognosis. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Dendrimer Conjugates Targeting Adenosine Receptors, P2Y Receptors and Other Receptors of the GPCR Superfamily, for Use in the Treatment of Various Disorders, Including Neurodegenerative Diseases, Stroke, Epilepsy, Pain and Thrombosis

Mon, 23 Mar 2009 15:00:00 GMT

Available for licensing and commercial development are conjugate compositions useful in the treatment of a variety of diseases, comprising a dendrimer and a ligand. The ligand is a functionalized congener of an agonist or antagonist of a receptor of the G-protein coupled receptor (GPCR) superfamily. More specifically, the invention focuses on several agonists and antagonists of A₁, A_2A, A_2B, and A₃ adenosine receptors and P2Y receptors, all members of the GPCR superfamily. For example, an agonist of the A₁ adenosine receptor is useful for treating a number of diseases including neurodegeneration, stroke, epilepsy, and pain. Antithrombotic treatment is another example of the use of this dendrimer technology. Dendrimers are polymers made from branched monomers through the iterative organic synthesis by adding one layer at each step to provide a symmetrical structure. Certain drugs, such as taxol, cisplatin, methotrexate, and ibuprofen, have been covalently linked to dendrimers in a reversible fashion. However, dendrimer conjugates in this application are biologically active without cleavage of the drug or cellular uptake. The conjugate of the invention can include any suitable dendrimer, particularly a poly(amidoamine) (PAMAM) dendrimer. The invention further provides pharmaceutical compositions and methods of treating various diseases and diagnostic methods employing such conjugates. CRADA Opportunity: The Laboratory of Bioorganic Chemistry of the National Institute of Diabetes & Digestive & Kidney Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize dendrimer conjugates of suitably functionalized small molecule ligands of adenosine receptors and P2Y nucleotide receptors. Please contact Dr. Kenneth A. Jacobson at 301-496-9024, or email kajacobs@helix.nih.gov, for more information.

Treatment of Schistosomiasis Using Substituted Oxadiazole 2-Oxides

Mon, 23 Mar 2009 19:00:00 GMT

Available for licensing and commercial development are pharmaceutical compositions and methods for the treatment of Schistosomiasis in mammals. The various compositions are based on a number of compounds derived from 1,2,5-oxadiazole that are potent inhibitors of thioredoxin glutathione reductase (TGR), a critical parasite redox protein.

Schistosomiasis is a chronic disease caused by trematode flatworms of the genus Schistosoma, including S. mansoni, S. japonicum and S. haematobium. Adult schistosome parasites live in an aerobic environment within human hosts, and therefore must have effective mechanisms to maintain cellular redox balance. Additionally, the worms must be able to evade reactive oxygen species generated by the host's immune response. In most eukaryotes there are two major systems to detoxify reactive oxygen species, one based on the tripeptide glutathione and the other based on the protein thioredoxin. Glutathione reductase (GR) reduces glutathione disulfide, whereas thioredoxin reductases (TrxR) are pivotal in the Trx-dependent system. It was recently discovered that specialized TrxR and GR enzymes are absent in schistosomes. Instead, they are replaced by the unique multifunctional enzyme TGR. This reliance on a single enzyme for both glutathione disulfide and thioredoxin reduction suggests that the parasite's redox systems are subject to a bottleneck dependence on TGR, and that TGR represents a potentially important drug target.

Schistosomiasis remains a major and neglected health problem in many tropical areas. The health burden resulting from Schistosomiasis is estimated to include more than 200 million people infected, 779 million at risk of infection, 280,000 deaths annually, and more than 20 million individuals experiencing high morbidity. Clinical manifestations of schistosomiasis infection include abdominal pain, cough, diarrhea, eosinophilia, fever, fatigue, and hepatosplenomegaly. The primary route of infection occurs through contact with infected river and lake water, at which time the parasite burrows into the skin, matures, then migrates to other areas of the body. Adult schistosome parasites reside in the mesenteric veins of their human hosts, where they can survive for up to 30 years. The need to control schistosomiasis is acute and efforts have been ongoing for years on three main fronts: prevention (via establishment and maintenance of sources of safe potable water), development of a vaccine, and use of drugs to treat the infection. CRADA Opportunity: The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/088,970. Please contact Dr. Craig J. Thomas via e-mail (craigt@nhgri.nih.gov) for more information.

Anti-Hepatitis C Virus Activity of the Protein Scytovirin (SVN)

Mon, 23 Mar 2009 23:00:00 GMT

The invention provides compositions and methods of use for potent anti-HCV protein scytovirin to prevent and treat HCV infections. Currently there is neither effective treatment nor vaccine against HCV infection and chronic HCV infection may lead to liver cancer and death. Scytovirin can be used alone or in combination with other anti-HCV drugs for HCV treatment and prevention. CRADA Opportunity: The National Cancer Institute CCR Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method of Making a Vaccine

Sat, 21 Mar 2009 03:00:00 GMT

Current invention describes the methods to prepare vaccines, and to use such vaccines in the vaccination and treatment of human disease, e.g., the human immunodeficiency virus (HIV) infections and cancer. More specifically, the present invention provides a vaccine and method for making same which is effective to elicit a desired antibody against a target antigen comprising a primary immunogen and a secondary immunogen, wherein the primary immunogen is effective to elicit B cell receptors (BCRs) that are on the maturational pathway of the desired antibody and have an intermediate degree of somatic mutational diversity, and the secondary immunogen comprises an epitope of the desired target antibody and is effective to further diversify the BCRs sufficient to form mature BCRs having the identical or substantially identical sequence as the desired antibody. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this method. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Prevention of Head and Neck Cancer Using Rapamycin and Its Analogs

Wed, 25 Feb 2009 08:00:00 GMT

It is frequently observed in head and neck squamous cell carcinoma (HNSCC), a cancer occurring mostly in the mouth, that the Akt/mTOR pathway is abnormally activated. Therefore, inhibiting this signaling pathway may help in treating this disease. Rapamycin and its analogs are known to inhibit the activity of mTOR so in principle they could serve as therapeutics for treating HNSCC.

Researchers at the NIH have developed a method of potentially preventing or treating HNSCC through the inhibition of mTOR activity. The proof of this principle was demonstrated by rapid regression of mouth tumors in mice afflicted with Cowden syndrome with the administration of rapamycin. Like HNSCC, development of this disease is linked to over activation of the Akt/mTOR pathway. Furthermore, the therapeutic potential of rapamycin was demonstrated using mice in experiments that model chronic exposure to tobacco, which promotes the development of HNSCC. Therefore, inhibitors of mTOR have considerable potential in the prevention and treatment of HNSCC. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Oral and Pharyngeal Cancer Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at bradleyda@nidcr.nih.gov for more information.

Compositions and Methods for Vaccine and Virus Production

Tue, 17 Feb 2009 13:00:00 GMT

This technology relates to compositions and methods for improving the growth characteristics of cells engineered to produce live viruses such as the Influenza virus. Featured is a method that uses the gene candidate, siat7e, or its expressed or inhibited products in Madin Darby Canine Kidney (MDCK) cells. The gene expression modulates anchorage-dependence of the cell line thereby allowing scale-up on bioreactor platforms without the use of microcarrier beads and reducing production costs. More specifically, this technology claims use of the methods embodied in the patent application for production of the Influenza viruses (human, avian and canine). CRADA Opportunity: The Biotechnology Core laboratory will consider collaborative research to further develop, evaluate, or commercialize the above invention. Please contact Dr. Joseph Shiloach at joseph.shiloach@nih.gov or 301-496-9719 for more information.

Microwave-Assisted Freeze Substitution of Biological and Biomedical Samples

Tue, 17 Feb 2009 18:00:00 GMT

Freeze substitution fixation (FS) of hydrated samples frozen in vitreous ice provides exceptional preservation of structure for light and electron microscopy, and enables immunological detection of thermo-labile antigens that otherwise are damaged/destroyed by processing at ambient or elevated temperatures. Its use as a research tool or in clinical pathology has, however, been limited by the relatively lengthy periods required for passive diffusion of fixatives and organic solvents into the frozen hydrated material.

The invention utilizes controlled microwave (MW) irradiation to accelerate the FS process; and comprises systems, devices and methods for microwave-assisted processing of samples under cryo-conditions. The entire MWFS procedure has been accomplished in less than 4 hours as compared to the approximately 2-5 days required for FS. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Research Technologies Branch, Electron Microscopy Unit, is interested in collaborative research to further develop, evaluate, or commercialize potential applications of this invention, including design and development of instrumentation for conducting MWFS. Please contact Barry U. Buchbinder, Ph.D., NIAID/OTD, at 301-594-1696 or bbuchbinder@niaid.nih.gov, for more information.

In Vivo Quantitative Tissue Oxygen Imaging Using Pulsed Time-Domain Electron Paramagnetic Resonance - Echo-based Single Point Imaging (ESPI)

Tue, 17 Feb 2009 23:00:00 GMT

Available for licensing and commercial development are patent rights covering an EPR image formation strategy for in vivo imaging of physiological function. It emphasizes image resolution and quantitative assessment of in vivo tissue oxygen that are important in planning radiation and chemotherapeutic treatments for patients with cancers. The method pertains exclusively to time-domain Fourier Transform EPR imaging (FT-EPRT) with emphasis on spatial and temporal resolution, since physiological processes are generally rapid and require accurate and rapid time-course information.

Two most important existing methods are Spin Echo Fourier (SEF) and Single Point Imaging (SPI). ESPI (Echo-based Single Point Imaging) enables the combination of the advantages of the quantitative T2 contrast of SEF strategy and the super high resolution of the SPI methodology, leading to reliable EPR imaging for tissue physiological function in vivo. CRADA Opportunity: The National Cancer Institute Radiation Biology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Echo-based Single Point Imaging. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Quantitative Real-Time RT-PCR Array for Detection of Human Herpesvirus 6A Gene Expression

Wed, 18 Feb 2009 04:00:00 GMT

This invention describes an RT-PCR array that allows for the simultaneous transcriptional profiling of the human herpesvirus HHV6A genome. It may be used to determine the contribution of HHV6A to the development of lymphomas, other types of cancer or diseases where an infectious agent is suspected. Primer pairs are designed to amplify under identical reaction conditions and are rigorously tested to ensure specificity for the HHV6A ORFs to the exclusion of all other human herpesviruses including HHV6B and HHV7.

Recent findings of the association of active viral genes with cancer cells have led to new proposed targets for cancer vaccines and therapeutics. The ability to distinguish HHV6A from other related herpesviruses, and to independently assay viral gene activity, may lead to the identification of new viral targets for the treatment of cancers and other diseases where HHV6A transcription is active. CRADA Opportunity: The National Cancer Institute, Advanced Technology Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize virus specific quantitative real-time RT-PCR arrays. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Sialostatin Mediation Controls Blood-feeding Success of the Tick Ixodes scapularis

Mon, 02 Feb 2009 09:00:00 GMT

This invention offers an environmentally friendly alternative to existing acaricides (pesticides), and relates to vaccines against tick bites and the pathogens that the ticks may transmit.

Bites from the nymphal stage of Ixodes scapularis are associated with Lyme disease transmission in disease-endemic areas of central and eastern US. Ixodes scapularis nymphs are the key vector stage implicated in Lyme disease transmission, mainly due to their small size that makes timely detection difficult. Guinea pig vaccination against sialostatin L2, a secreted Ixodes scapularis salivary protein, can confer nymphal recognition and protection against the tick. Increased rejection rates, prolonged feeding time, and inflammation were observed in the vaccine group, indicating that a protective host immune response was elicited. Moreover, anti-sialostatin L2 titers correlate with weight reduction of nymphs by the end of feeding. These studies suggest that an essential action of sialostatin L2 can be blocked by host humoral immunity. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases / Laboratory of Malaria and Vector Research / Vector Biology Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize potential applications based on the above mentioned patent and in regard to the protection from tick bites and the pathogens they transmit. Please contact Charles Rainwater, NIAID/OTD, at 301-435-8617/or crainwater@niaid.nih.gov for more information.

Humanized Monoclonal Antibodies that Specifically Bind Japanese Encephalitis Virus (JEV) and Their Use

Mon, 02 Feb 2009 14:00:00 GMT

Japanese encephalitis virus (JEV) is the prototype virus of the Japanese encephalitis (JE) group belonging to the Flavivirus genus of the Flaviviridae family. Other members of the group include Kunjin virus, St. Louis encephalitis virus, and West Nile encephalitis virus (WNV). JEV is widely distributed in South Asia, Southeast Asia, and the Asian Pacific Rim. In recent years, JE epidemics have spread to previously unaffected areas, such as northern Australia, Pakistan, India and Indonesia. The JE outbreak in India during July to November of 2005 was the longest and most severe in recent years, affecting more than 5,000 persons and causing more than 1,000 deaths. It is estimated that JEV causes 35,000 to 50,000 cases of encephalitis, including 10,000 deaths and as many neurologic sequelae, each year. The wide geographical distribution and the existence of multiple strains, coupled with the high rate of mortality and residual neurological complications in survivors, make JEV infection an important public health problem. Until a JEV vaccine becomes generally available, passive immunization with potently neutralizing anti-JEV antibodies remains an attractive strategy for short-term prevention of and therapeutic intervention in encephalitic JEV infections.

From a panel of 11 Fabs recovered by different panning strategies, three highly potent neutralizing antibodies, termed Fabs A3, B2, and E3, which recognized spatially separated regions on the JEV virion were identified. These antibodies reacted with epitopes in different domains: the major determinant for Fab A3 was Lys179 (domain I), that for Fab B2 was Ile126 (domain II), and that for Fab E3 was Gly302 (domain III) in the envelope protein, suggesting that these antibodies neutralize the virus by different mechanisms. These three Fabs and derived humanized monoclonal antibodies (MAbs) exhibited high neutralizing activities against a broad spectrum of JEV genotype strains. In preclinical testing, the monoclonal antibodies of the technology significantly prolonged the average survival time compared to the control group, suggesting a therapeutic potential for use of MAb B2 in humans.

This application claims the antibodies described above, methods of preventing and/or treating JEV with the antibodies, and diagnostics using the antibodies of the technology. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "Humanized Monoclonal Antibodies that Specifically Bind Japanese Encephalitis Virus (JEV) and Their Use". Please contact Percy Pan at 301-451-3523 for more information.

Adoptive Immunotherapy for Reestablishing HIV-specific Cytotoxic T-cell (CD8 T-cell) Function in HIV and AIDS Patients and Methods for Assessing the Reestablishment of CD8 T-cell Function

Mon, 02 Feb 2009 19:00:00 GMT

This technology includes methods and compositions for rescuing or reestablishing the ability of HIV-specific, cytotoxic T-cells (CD8 T-cells) to proliferate and kill HIV-infected cells such as CD4 cells. Additionally, this invention provides a means for evaluating the ability of therapeutic vaccines or other therapies to reestablish CD8 T-cell function during HIV infection. As an immunotherapy, this technology involves treating peripheral blood mononuclear cells (PBMCs) from an HIV or AIDS patient to reestablish CD8 T-cell function and returning the treated cells to the patient. It is anticipated that this technology could provide an alternative to antiretroviral therapy (ART).

Background:
This technology arose from research aimed at understanding why HIV infection does not progress in a subset of HIV-infected individuals, called long-term nonprogressors (LTNP). During the course of HIV infection HIV-specific CD8 T-cells from HIV progressors lose the ability to proliferate and kill HIV-infected cells using cytotoxins such as perforin and granzymes A and B. Unlike HIV progressors, it has been shown that CD8 T-cells from LTNP retain the ability to proliferate and use cytotoxins to kill HIV-infected cells. This technology provides a means for rescuing HIV-specific CD8 T-cell proliferation and cytotoxic functions in HIV progressors. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Richard Williams at 301-451-3522 for more information.

HTLV-II Vector and Methods of Use

Tue, 03 Feb 2009 00:00:00 GMT

The invention hereby offered for licensing is in the field of vaccines and vaccine vectors. More specifically the invention provides compositions and methods of use of HTLV-II viral vector. The vector comprises at least a portion of the HTLV-II genome encoding the gag, pro, and pol genes and lacking all or a portion of the pX region. A heterologous gene is inserted within the deletion of the pX region. The gene of interest may encode all or a portion of a protein that corresponds to a viral protein of a foreign virus. The viral vectors thus constructed are useful for inducing immune response to the viral protein from the foreign virus. In particular the invention claims vaccines against HIV and SIV. CRADA Opportunity: The National Cancer Institute, Animal Models & Retroviral Vaccine Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HTLV-II vectored HIV vaccines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Mouse Monoclonal Antibodies to MAD1, a Human Spindle Assembly Checkpoint Protein for Maintaining Chromosomal Segregation

Mon, 02 Feb 2009 05:00:00 GMT

Scientists at the National Institutes of Health have developed mouse monoclonal antibodies against the human spindle assembly checkpoint protein, MAD1. The spindle assembly checkpoint in mitotic cell division regulates the fidelity of chromosome segregation during cell division. MAD1 is an important component of this checkpoint control, which if compromised, can lead to the initiation of cancer cell growth. These monoclonal antibodies are the first available antibodies against MAD1 and can be used in laboratory research and diagnostics. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize reagents for studying cell cycle checkpoint factors. Please contact Agnes Rooke at rookeab@niaid.nih.gov or by phone at 301-594-1697 for more information.

Novel Protein Delivery System for Mammalian Cells

Mon, 02 Feb 2009 10:00:00 GMT

Virus-like particles (VLPs) consist of viral structural proteins that are capable of self-assembly into a nanoparticle, but are non-infectious because they lack viral nucleic acids. VLPs have been used in viral vaccines, such as those for human papilloma virus and hepatitis B. However, they also have great potential in other applications, such as cancer vaccines, transport of nucleic acids into target cells (gene therapy), and transport of biologics or other large molecules into target cells for therapeutic purposes. The present technology discloses a chimeric VLP containing a GAG-Cre recombinase fusion protein. This recombinase fusion protein retains Cre recombinase activity, and can excise a LOX-flanked gene in a transduced target cell. Experiments by Drs. Kaczmarczyk and Chatterjee have demonstrated that chimeric VLPs can be used to deliver functional fusion proteins into cells. The technology also provides for a two-VLP protein delivery system designed to deliver a protein of interest into a target cell. The present technology also discloses VLPs containing GAG-protein of interest (ex. GAG-Cre) co-packaged with GAG-protease to deliver protein of interest in target site as a fully-processed protein rather than as a fusion protein.

The claims in the pending patent application provide for virus like particles, methods of making virus like particles, and methods of using virus like particles to deliver proteins to a cell. The claims also provide for methods of targeting a protein to a cell, methods of protein therapy and methods of treating diseases or disorders. CRADA Opportunity: The National Cancer Institute Advanced Technology Program, Protein Expression Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Substituted IL-15

Mon, 02 Feb 2009 15:00:00 GMT

Interleukin-15 (IL-15) is an immune system modulating protein (cytokine) that stimulates the proliferation and differentiation of T- lymphocytes. In the clinical context, IL-15 is being investigated for use in the treatment of diseases such as cancer. In vitro manufacture of IL-15 can be problematic.

The invention relates to substituted IL-15 amino acid sequences of one or more amino acids that are predicted to reduce or eliminate deamidation of a specific aspargine amino acid residue found within the IL-15 protein. Deamidation can lead to protein degradation and interfere with the pharmaceutical purification and processing of IL-15. The invention also provides potential substituted gene sequences that encode the substituted IL-15 amino acid sequences. The substituted IL-15 amino acid sequences may advantageously facilitate the refolding, purification, storage, characterization, and clinical testing of IL-15. CRADA Opportunity: The National Cancer Institute Biological Research Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the topic of this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

HMGN Polypeptides as Immune Enhancers and HMGN Antagonists as Immune Suppressants

Mon, 02 Feb 2009 20:00:00 GMT

HMGN polypeptides are multidomain proteins known to function by binding DNA to regulate the transcription of certain genes inside cells. However, when a HMGN polypeptide is released extracellularly, it distinctly acts as a potent activator of the immune system. Because of this activity, it has potential use as a biological therapeutic for stimulating an immune response as well as a promising target for antagonist drugs to suppress a pathological inflammatory response.

Secreted HMGN acts as a potent recruiter and activator of dendritic cells, the cell principally responsible for initiating the immune response. Furthermore, it enables dendritic cells to preferentially induce a Th1-type T lymphocyte response that leads to enduring cellular immunity. Therefore, HMGN has potential use as a clinically effective immunoadjuvant for use in vaccines against tumors and many intracellular pathogens.

Investigators at the National Institutes of Health have developed compositions and methods for using HMGN and its derivatives as immunoadjuvants in combination, as mixtures or as chemical conjugates, with microbial or tumor antigens. HMGN has the advantage of being gene encoded so it can be fused to an antigen gene to produce recombinant fusion proteins or administered as a DNA vaccine. Conversely, HMGN could be exploited as a drug target to treat diseases that would benefit from shifting away the Th1-type immune response towards a Th2-type or humoral immune response. This would be beneficial for treatment of parasitic infections and inflammatory or autoimmune disorders. CRADA Opportunity: The National Cancer Institute Laboratory of Molecular Immunoregulation is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HMGN1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Prognostic Test for Breast Cancer Based on a 12 Gene Expression Signature

Tue, 03 Feb 2009 01:00:00 GMT

The clinical course and survival times of patients with breast cancer varies greatly, consequently it is difficult to establish a prognosis for the disease. To improve patient prognosis, much effort has been made to identify biological markers that would allow precise staging of the cancer. When cells cannot repair minor damage to their DNA it leads to genetic instability which can produce gross abnormalities in chromosomes and the onset of a cancer. It is known that the magnitude of the abnormalities is strongly correlated with a negative prognosis for cancer. Thus, genetic instability can serve as a useful biomarker for establishing a prognosis for breast cancer patients. Presently, genetic instability is not directly accounted for in established prognostic tests.

Investigators at the National Cancer Institute (NCI) have developed a compact gene signature that detects genome instability in breast cancer cells. By comparing changes in expression levels of only 12 genes in malignant tissue to levels in normal breast tissue it is possible to detect the genetic abnormalities that are indicative of a poor prognosis. This method has potential to improve markedly the forecasting of clinical outcomes for breast cancer and help improve treatment of this disease. CRADA Opportunity: The National Cancer Institute Genetics Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Prognostic Test for Breast Cancer Based on a 12 Gene Expression Signature. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Attenuated Salmonella as a Delivery System for siRNA-Based Tumor Therapy

Fri, 09 Jan 2009 06:00:00 GMT

The discovery that genes vectored by bacteria can be functionally transferred to mammalian cells has suggested the possible use of bacterial vectors as vehicles for gene therapy. Genetically modified, nonpathogenic bacteria have been used as potential antitumor agents, either to elicit direct tumoricidal effects or to deliver tumoricidal molecules. Bioengineered attenuated strains of Salmonella enterica serovar typhimurium (S. typhimurium) have been shown to accumulate preferentially greater than one-thousand fold in tumors than in normal tissues and to disperse homogeneously in tumor tissues. Preferential replication allows the bacteria to produce and deliver a variety of anticancer therapeutic agents at high concentrations directly within the tumor, while minimizing toxicity to normal tissues. These attenuated bacteria have been found to be safe in mice, pigs, and monkeys when administered intravenously, and certain live attenuated Salmonella strains have been shown to be well tolerated after oral administration in human clinical trials. The S. typhimurium phoP/phoQ operon is a typical bacterial two-component regulatory system composed of a membrane-associated sensor kinase (PhoQ) and a cytoplasmic transcriptional regulator. phoP/phoQ is required for virulence, and its deletion results in poor survival of this bacterium in macrophages and a marked attenuation in mice and humans. phoP/phoQ deletion strains have been employed as effective vaccine delivery vehicles. More recently, attenuated salmonellae have been used for targeted delivery of tumoricidal proteins.

This technology comprises live, attenuated Salmonella strains as a delivery system for small interfering double-stranded RNA (siRNA)-based tumor therapy. The inventors' data provide the first convincing evidence that Salmonella can be used for delivering plasmid-based siRNAs into tumors growing in vivo. Claimed in the related patent application are methods of inhibiting the growth or reducing the volume of solid cancer tumors using the si-RNA constructs directed against genes that promote tumor survival and cancer cell growth. The Stat3-siRNAs carried by an attenuated S. typhimurium described in the application exhibit tumor suppressive effects not only on the growth of the primary tumor but also on the development of metastases, suggesting that an appropriate attenuated S. typhimurium combined with the RNA interference (RNAi) approach may offer a clinically feasible method for cancer therapy. CRADA Opportunity: FDA-CBER Division of Bacterial, Parasitic, and Allergenic Products is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Salmonella-delivered anti-tumor therapies or Salmonella-vectored vaccines. Please contact Alice Welch at Alice.Welch@fda.hhs.gov for more information.

Method of Treating Pneumoconiosis with Oligodeoxynucleotides

Fri, 09 Jan 2009 11:00:00 GMT

The inhalation of dust containing crystalline silica particles causes silicosis, an incurable lung disease that progresses even after dust exposure ceases. The World Health Organization estimates that over a million US workers are exposed to silica dust annually, and that thousands worldwide die each year from silicosis. The pulmonary inflammation caused by silica inhalation is characterized by a cellular infiltrate and the accumulation of chemokines, cytokines (including TNF-alpha, IL-1, and IL-6), and Reactive Oxygen Species (ROS) in bronchoalveolar lavage (BAL) fluid.

Macrophages are the predominant immune cell type present in alveolar spaces where they play an important role in the lung pathology associated with silica inhalation. The uptake of silica particles by macrophages triggers the production of ROS (including hydrogen peroxide) via the oxidative stress pathway, which in turn contributes to pulmonary damage and macrophage death.

One potential strategy for limiting the production of proinflammatory cytokines and ROS after silica exposure involves treatment with "suppressive" oligonucleotides (ODN). Suppressive ODN express motifs based on the repetitive TTAGGG hexamers present at high frequency in the telomeric ends of self DNA. Previous studies showed that these motifs (released by injured host cells) block Th1 and proinflammatory cytokine production in vitro and down-modulate over-exuberant/pathologic immune responses in vivo (such as those found in septic shock and autoimmune diseases).

This application claims methods for treating, preventing or reducing the risk of developing occupational lung diseases using. Preclinical in vivo studies show that pretreatment with suppressive (but not control) ODN reduces silica-dependent pulmonary inflammation. Preclinical in vivo studies also showed that treatment with suppressive ODN also reduced disease severity and improved the survival of mice exposed to silica. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Method of Treating Pneumoconiosis with Oligodeoxynucleotides. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of Mono-Amine Oxidase Inhibitors to Prevent Herpes Virus Infections and Reactivation from Latency

Fri, 09 Jan 2009 16:00:00 GMT

Available for licensing are methods of using Monoamine Oxidase Inhibitors (MAOIs) to prevent alpha-herpesvirus lytic infections, such as those caused by Herpes simplex virus (HSV-1 or HSV-2) and Varicella zoster virus (VZV), and to possibly prevent the periodic reactivation of these viruses from latency. MAOIs have been historically used to treat depression, hypertension, and related diseases. The invention describes how MAOIs can also inhibit LSD1, a histone/protein demethylase that is required for initiation of alpha-herpesvirus lytic infection. After an initial lytic infection, alpha-herpesviruses establish latent infections in sensory neurons and undergo periodic reactivation that results in disease ranging from mild lesions to life threatening encephalitis. Investigators have determined that MAOIs may also block the reactivation process. Due to the nature of the target LSD1 and its role in modulating chromatin modifications, these drugs could also prevent infection by or reactivation of other nuclear viruses.

Alpha-herpesviruses infections are common worldwide, with 57% to 80% of adults being seropositive for HSV. Recurrent labial herpes affects roughly one third of the U.S. population, and these patients typically experience 1 to 6 episodes per year. Genital herpes can result from infection with either HSV type and HSV-1 has become an important cause of genital herpes in some developed countries. HSV keratitis is the most frequent cause of corneal blindness in the United States, is a leading indication for corneal transplantation, and is the most common cause of infectious blindness in the Western world. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases' Laboratory of Viral Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of MAOIs to prevent herpes virus infections and reactivation from latency. Please contact Thomas Kristie, PhD at 301.496.3854 or tkristie@niaid.nih.gov for more information.

Recombineering Vector

Mon, 05 Jan 2009 21:00:00 GMT

Transgenic mouse models have become a common experimental tool for unraveling gene function. Bacterial artificial chromosome (BAC) mediated transgenesis has proven to be a highly reliable way to obtain accurate transgene expression for in vivo studies of gene expression and function. A rate-limiting step in characterizing large numbers of genes by this approach has been the speed and ease by which BACs can be modified. NIH investigators have developed a highly efficient recombineering vector that can be used for modifying BACs in bacteria. This new vector contains tetracycline and chloramphenical resistance as well as the ccdB gene that encodes a protein that interferes with E. coli DNA gyrase. This vector can be propagated in ccdB resistant E. coli strains but not in other strains (DH5a, Top10, DH10B, etc) unless the ccdB is replaced by DNA inserts flanked by attB1 and attB2 sites. This vector was generated to modify BAC plasmids by RecA-mediated recombination.

The vector disclosed here bypasses the rate-limiting step in recombineering protocols; the efficient cloning of a modifying vector. It is well suited for efficient production of engineered BACs for use in a variety of in vivo studies. CRADA Opportunity: The NIAMS/NIH Genomics and Immunity group is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the engineering of mouse transgenic constructs using the new vector and BAC recombineering. Please contact Rafael Casellas, Ph.D. at 301-402-7858 or email to casellar@mail.nih.gov for more information.

Knockout of Aryl Hydrocarbon Receptor (AhR) and its Binding Partner Aryl Hydrocarbon Receptor Nuclear Translocator (Arnt) each in Separate Mouse Models

Tue, 06 Jan 2009 02:00:00 GMT

The technology relates to two separate knockout mouse models of related transcription factors that bind each other. The aryl hydrocarbon receptor (AhR) and the aryl hydrocarbon receptor nuclear translocator (Arnt) protein are transcription factors that play an important role in mediating the effects of man-made environmental toxins. They also play a role in mammalian development and physiological homeostasis. Members of the PAS domain/bHLH family of transcription factors, they are obligate dimerization partners with each other and other members of this family, such as hypoxia-inducible factor 1alpha (HIF1alpha). These transcription factors have been shown to be important in a number of specific tissues including ovary, vascular endothelium, keratinocytes, T-cells, and liver.

Available for licensing is a knockout mouse line in which the AhR receptor has been knocked-out, and a mouse line containing a floxed allele of the Arnt gene. The Arnt mouse line can be used to disrupt the Arnt gene in different tissues by breeding the Arnt-floxed mice with transgenic mice in which the Cre recombinase is under the control of tissue-specific promoters. These mice may be used as a research tool for drug development where PAS/bHLH transcription factors are targeted. CRADA Opportunity: The National Cancer Institute, Laboratory of Metabolism, Center for Cancer Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method for Predicting and Detecting Tumor Metastasis

Mon, 05 Jan 2009 07:00:00 GMT

Detecting cancer prior to metastasis greatly increases the efficacy of treatment and the chances of patient survival. Although numerous biomarkers have been reported to identify aggressive tumor types and predict prognosis, each biomarker is specific for a particular type of cancer, and no universal marker that can predict metastasis in a number of cancers have been identified. In addition, due to a lack of reliability, several markers are typically required to determine the prognosis and course of therapy.

The inventors discovered a novel CPE splice variant designated CPE-deltaN and found its expression levels increase according to the presence of cancer and metastasis wherein this variant is upregulated in tumors and further increased in metastatic cancer. This data has been demonstrated both in vitro and in vivo experiments and in liver, breast, prostate, colon, and head and neck cancers. Metastatic liver cells treated with CPE-deltaN siRNA reversed the cells from being metastatic and arrested cells from further metastasis. Thus, this novel CPE isoform is a biomarker for predicting metastasis and its inhibitors have an enormous potential to increase patient survival. CRADA Opportunity: The National Institute of Child Health and Human Development, Laboratory of Development Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Method for Predicting and Detecting Tumor Metastasis. Please contact Joseph M. Conrad, LD, PhD, at 301-435-3107 or jmconrad@mail.nih.gov for more information.

Novel Inhibitor of NF-kappa B Pathway

Mon, 05 Jan 2009 12:00:00 GMT

Many tumors and blood cell cancers show overactivation of the NF-kappa B signal transduction pathway. This overactivation is associated with cancer forming in the colon, liver and other epithelial sites. In addition, there is evidence that overactivation leads to tumor formation and metastasis. However, this pathway is key for normal immunity, so any inhibition of NF-kappa B overactivation must avoid diminishing the body’s ability to fight infection.

This invention claims a compound that inhibits NF-kappa B activation without affecting other transcription factors such as AP-1 and SRE binding proteins. It appears to function by blocking IKK beta and is effective at low micromolar concentrations without affecting cell proliferation or cell survival. At this low concentration, NF-kappa B is reduced to basal levels so this novel compound has prospects for preventing or treating cancer without being detrimental to immunity. In addition, because NF-kappa B overactivation contributes to a variety of inflammatory disorders including colitis, diabetes, prostatitis, and pancreatitis this compound has therapeutic applications beyond cancer. CRADA Opportunity: The National Cancer Institute (SAIC-Frederick) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize around development of analogs and/or further investigations of mechanism of action of the compound. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method of Promoting Hematopoietic Stem Cell Engraftment by Enhancement of CXCR4 Activity

Thu, 01 Jan 2009 17:00:00 GMT

The success of allogeneic Hematopoietic Stem Cell (HSC) transplant is dependent upon factors affecting engraftment of donor HSC. Engraftment is affected by type and intensity of bone marrow conditioning and immunosuppression achieved by chemotherapy or radiation treatments as well as the number of stem cells present in the graft. Factors influencing HSC trafficking, such as HSC chemotaxis and adhesion, modulate the ability of HSCs to engraft in the transplant recipient. Chemokine receptor CXCR4 (present on HSC) and its ligand, SDF-1, play an important role in attracting HSC to and retaining HSC in the bone marrow after transplantation. Studies indicate that with increased amounts of CXCR4 in human HSC there is a several fold increase in the engraftment of HSCs in a xenograft mouse transplant model.

This technology is directed to compositions comprising HSCs and methods for promoting CXCR4 expression in a HSC by inhibiting GRK3 or GRK6 (G-protein coupled receptor kinase (GRK) regulators of CXCR4) with an antisense compound. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Host Defenses, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a method to improve hematopoietic stem cell transplantation through the enhancement of CXCR4 activity. Please contact Rosemary C. Walsh, Ph.D. at 301-451-3528 or rcwalsh@niaid.nih.gov for more information.

A Novel and Efficient Technology for Targeted Delivery of siRNA

Thu, 01 Jan 2009 22:00:00 GMT

The biological phenomenon of RNA interference (RNAi) has much promise for developing therapeutics to a variety of diseases. However, development of RNAi therapies remains mainly in preclinical stages largely because of difficulties in delivering small inhibitory RNAs (siRNA) and short hairpin RNAs (shRNA) into target cells. Although viral vector-based siRNA delivery systems have been widely used, their specificity and safety remains significant issue. Without a solution to this delivery problem, RNAi cannot fulfill its therapeutic promise.

Investigators at the National Institutes of Health have developed novel compositions and methods for delivering inhibitory oligonucleotides to cells in a targeted and efficient manner. The compositions and methods are based on utilizing a cell surface receptor targeting ligand, such as cytokine or chemokine, and a domain that binds an inhibitory oligonucleotide, to efficiently deliver the inhibitory oligonucleotide to the cell that expresses the cell surface receptor targeting ligand. Chemokine receptors are differentially expressed on various cells, including tumors; hence this technology allows targeting siRNA to aberrant cells. Gene silencing can also be achieved in variety of immune cells by targeting cytokine receptors. This technology has great potential for developing into a safe and effective means of delivering therapeutic siRNAs. CRADA Opportunity: The National Institute on Aging, Immunotherapeutics Unit, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize chemokine-based siRNA/shRNA technology for treatment of cancers and autoimmune diseases, i.e. to control expression of immunomodulatory cytokines and other factors that facilitate tumor escape, activity of regulatory T cells or Th2 type of cells. This technology can be also utilized to boost vaccine responses against cancers and chronic infectious diseases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Monoclonal Antibodies to the Tumor-Specific Antigen, Human ROR1

Fri, 02 Jan 2009 03:00:00 GMT

B-cell chronic lymphocytic leukemia (B-CLL) is an incurable disease developed by more than 15,000 Americans each year and currently, there are no therapeutic monoclonal antibodies (mAbs) that specifically recognize B-CLL tumor cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a constitutively expressed tumor-specific cell surface antigen and an ideal target for therapeutic antibodies.

Available for licensing are four mouse anti-human ROR1 mAbs (hybridomas designated 2A2, 2D11, 1A1, and 1A7). All four mAbs bind specifically to the extracellular domain of human ROR1 and have good potential for therapeutic development by either humanization, conversion to chimeric mouse/human antibodies, or conjugation to a radioisotope, chemical drug or bacterial toxin. CRADA Opportunity: The National Cancer Institute, Experimental Transplantation and Immunology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostic or therapeutic mAbs against ROR1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Mice with a Conditional LoxP-Flanked Glucosylceramide Synthase Allele Controlling Glycosphingolipid Synthesis

Thu, 01 Jan 2009 08:00:00 GMT

Glycosphingolipids are organizational building blocks of plasma membranes that participate in key cellular functions, such as signaling and cell-to-cell interactions. Glucosylceramide synthase - encoded by the Ugcg gene - controls the first committed step in the major pathway of glycosphingolipid synthesis. Global disruption of the Ugcg gene in mice is lethal during gastrulation. The inventors have established a Ugcg allele flanked by loxP sites (floxed). When cre recombinase was expressed in the nervous system under control of the nestin promoter, the floxed gene underwent recombination, resulting in a substantial reduction of Ugcg expression and of glycosphingolipid ganglio-series levels. The mice deficient in Ugcg expression in the nervous system show a striking loss of Purkinje cells and abnormal neurologic sphingo-lipid behavior.

The Research Tools available are mice with a floxed Ugcg allele that can be deleted in a conditional manner. These mice carrying floxed Ugcg alleles will be useful for delineating the functional roles of glycosphingolipid synthesis in the nervous system and in other physiologic systems.

CRADA Opportunity: The NIDDK Genetics of Development and Disease Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the sphingolipid metabolism in physiology and disease. Please contact Dr. Proia at proia@nih.gov for more information.

Method for Predicting and Detecting Tumor Metastasis

Mon, 15 Dec 2008 13:00:00 GMT

Detecting cancer prior to metastasis greatly increases the efficacy of treatment and the chances of patient survival. Although numerous biomarkers have been reported to identify aggressive tumor types and predict prognosis, each biomarker is specific for a particular type of cancer, and no universal marker that can predict metastasis in a number of cancers have been identified. In addition, due to a lack of reliability, several markers are typically required to determine the prognosis and course of therapy.

Available for licensing are carboxypeptidase E (CPE) inhibitor compositions and methods to prognose and treat cancer as well as methods to determine the stage of cancer. The inventors discovered that CPE expression levels increase according to the presence of cancer and metastasis wherein CPE is upregulated in tumors and CPE levels are further increased in metastatic cancer. This data has been demonstrated both in vitro and in vivo experiments and in liver, breast, prostate, colon, and head and neck cancers. Metastatic liver cells treated with CPE siRNA reversed the cells from being metastatic and arrested cells from further metastasis. Thus, CPE as a biomarker for predicting metastasis and its inhibitors have an enormous potential to increase patient survival. CRADA Opportunity: The National Institute for Child Health and Human Development, Section on Cellular Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize CPE as a biomarker for predicting metastasis. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Anti-Plasmodium Compositions and Methods of Use

Mon, 01 Dec 2008 18:00:00 GMT

The present invention comprises peptides/antibodies specific for the binding proteins of Plasmodium, a parasite responsible for malaria, hence in effect blocking the parasite’s binding to the erythrocytes. Also included are methods for their use in preventing, diagnosing or treating the related infections.

Although malaria is virtually eradicated in the United States, it continues to be one of the most serious infectious diseases in the world, killing millions of people each year in the countries throughout Africa, Asia and Latin America. In fact, over 41% of the world population lives in the regions affected by malaria. In vitro studies using the antibodies described in the current technology showed ~80% reduction in the number of blood cells infected with Plasmodium parasite. Infectivity studies using peptides demonstrated that they are also specifically able to prevent binding of parasites to blood cells. The claimed antibodies and peptides can also be used for immunization of humans and animals, or for development of diagnostic kits capable of detecting the presence, localization and quantity of the Plasmodium parasites in tissues and cells. CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "Anti-Plasmodium Compositions and Methods of Use." Please contact Dana Hsu at 301-496-2400 for more information.

Discovery of Novel Pharmacophores Inhibiting the Growth of Mycobacterium tuberculosis

Mon, 01 Dec 2008 23:00:00 GMT

Tuberculosis (TB) caused by Mycobacterium tuberculosis infects roughly one third of the world population and approximately 8 million people develop TB annually. The emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) TB strains highlight the need for new drugs against TB. The inventions described herein are small molecules with drug-like properties that inhibit the growth of Mycobacterium tuberculosis. The compounds were discovered utilizing high-throughput screening of a 101,000 compound library. Three hundred active compounds inhibit Mycobacterium tuberculosis growth by 90% or greater in in vitro assays with MIC values ranging from 1.6 to less than 0.1 micrograms/ml, and showing minimal toxicity in tissue culture cells. Structure similarity analyses of the compounds reveal 44 chemical clusters representing 250 active compounds. CRADA Opportunity: The NIAID, OTD, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this "Discovery of Novel Pharmacophores Inhibiting the Growth of Mycobacterium Tuberculosis". Please contact Anna Amar at 301-451-3525 for more information.

A Novel, Non-Invasive and Therapeutically Useful High Throughput Technique to Isolate Highly Enriched Tumor Reactive Lymphocytes from Peripheral Blood - Potential Use in Adoptive Immunotherapy

Tue, 02 Dec 2008 04:00:00 GMT

The adoptive transfer of autologous antigen reactive lymphocytes has been shown to mediate significant tumor regression in some patients with metastatic cancer. However, the isolation of these T lymphocytes requires invasive surgery, which can lead to post-operative complications and delays in initiating adoptive immunotherapy with T cells.

This technology is directed to the use of a novel high throughput technique to isolate highly enriched tumor reactive lymphocytes in a non-invasive manner from the peripheral blood of cancer patients for the purpose of cancer immunotherapy. The technique utilizes a highly sensitive PCR based screening assay. CRADA Opportunity: The National Cancer Institute, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this high throughput T cell isolation technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Ectopic Thymidylate Synthase Accelerates the Development of Hyperplastic Foci and Adenomas in Pancreatic Islets

Mon, 01 Dec 2008 09:00:00 GMT

Thymidylate synthase (TS) is an E2F1-regulated enzyme essential for DNA synthesis and repair. Elevated levels of TS protein and mRNA levels are associated with many human cancers. Previous research by the NIH inventors has demonstrated that ectopic expression of catalytically active TS is sufficient to induce a transformed phenotype in mammalian cells as manifested by foci formation, anchorage independent growth, and tumor formation in nude mice. Overexpression of hTS in murine islets provides a model to study genetic alterations associated with the progression from normal cells to hyperplasia and adenoma and suggests that this mouse model may be useful for cancer prevention and the development of therapeutic strategies. CRADA Opportunity: The National Cancer Institute, Medical Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Thymidylate Synthase Transgenic Animal Model. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method for Detection of Cancer Based on Spatial Genome Organization in the Cell Nucleus

Mon, 01 Dec 2008 14:00:00 GMT

The successful treatment of cancer is correlated with the early detection of the cancerous cells. Conventional cancer diagnosis is largely based on qualitative morphological criteria, but more accurate quantitative tests could greatly increase early detection of malignant cells. It has been observed that the spatial arrangement of DNA in the nucleus is altered in cancer cells in comparison to normal cells. Therefore, it is possible to distinguish malignant cells by mapping the position of labeled marker genes in the nucleus.

This NIH invention provides methods of detecting abnormal cells in a sample using the spatial position of one or more genes within the nucleus of a cell, as well as a kit for detecting abnormal cells using such methods. The invention also provides methods of identifying gene markers for abnormal cells using the spatial position of one or more genes within the nucleus of a cell. CRADA Opportunity: The National Cancer Institute, Cell Biology of Genomes Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostic methods for detection of cancer using spatial genome organization. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Compositions and Methods for Inhibition of Fat-Specific Protein 27

Mon, 01 Dec 2008 19:00:00 GMT

FSP27 expression is regulated by PPARgamma, a gene known to play a critical role in the development of fatty liver. Over-expression of FSP27 results in an increase in triglyceride accumulation and an increase in cystolic vacuoles containing lipid droplets which are associated with development of fatty liver disease or hepatic steatosis. This abnormal retention of lipids in liver cells occurs in diabetes and alcoholism and is correlated with decreased liver function which can often lead to cirrhosis and sometimes death. Presently, there are no adequate therapies for fatty liver disease.

This technology is directed towards compositions and methods of inhibiting FSP27, which include antisense compounds, small molecule inhibitors and antibodies that target FSP27. CRADA Opportunity: The Laboratory of Metabolism, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of FSP27 for treatment of fatty liver disease. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Varicella-Zoster Virus Mutant that is Markedly Impaired for Latent Infection Available for the Development of Shingles Vaccines and Diagnostics

Tue, 02 Dec 2008 00:00:00 GMT

Reactivation of latent Varicella-Zoster virus (VZV) infection is the cause of shingles, which is prominent in adults over the age of 60 and individuals who have compromised immune systems, due to HIV infection, cancer treatment and/or transplant. Shingles is a worldwide health concern that affects approximately 600,000 Americans each year. The incidence of shingles is also high in Europe, South America, and India; the latter having an estimated two million individuals affected, yearly. Recent research studies show that VZV vaccines have a significant effect on decreasing the incidence of shingles in elderly.

The current technology describes compositions, cells and methods related to the production and use of a mutant VZV and the development of vaccines against the infectious agent. Latent VZV expresses a limited repertoire of viral genes including the following six open reading frames (ORFs): 4, 21, 29, 62, 63, and 66. The present invention describes an ORF29 mutant VZV that demonstrates a weakened ability to establish latency in animal studies. The current technology provides methods for using the mutant in the development of live vaccines and diagnostic tools. A related invention is described in PCT/US05/021788 (publication number WO2006012092). CRADA Opportunity: The NIAID Laboratory of Clinical Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize vaccine strains of VZV vaccine with impaired latency. Please contact Jason Freeman, J.D., at 301/451-5054 or freemanch@mail.nih.gov for more information.

Methods and Compositions for Selectively Enriching Microbes

Mon, 01 Dec 2008 05:00:00 GMT

The described technology provides markedly improved enrichment of E. coli O157:H7, Shiga toxin-producing E. coli (STEC) and Shigella. This improved enrichment can be complimentary to, and enhance performance of, existing nucleic acid or antibody based detection methods. In addition, the improved enrichment method facilitates isolation of pathogens following positive results by any nucleic acid or antibody based test. Such isolation by cultural methods is essential for epidemiology, antibiotic sensitivity testing and other biochemical characterization.

Current enrichment protocols are often inadequate as they allow large numbers of interfering bacteria to grow. This makes it necessary for microbiologists to screen hundreds of presumptive colonies to achieve successful isolation (A Khan et al., Emerg Infect Dis. 2002 Jan; 8:54-62). The new technology is a simple two step process. The sample is first placed in a low pH solution for a brief period and then transferred to a medium permitting maximal growth of target bacteria. With this new technology there is no risk of false negative results due to inadvertent inhibition of target bacteria by novobiocin, tellurite, cefixime, or other additives commonly used in existing enrichment procedures.

This new technology has been shown to be effective with food, water, environmental and clinical samples. Its components are inexpensive and microbiologists are not required to impede their workflow by adding separate selective agents at specified intervals such as four or six hours. CRADA Opportunity: The FDA is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods for detecting pathogenic bacteria, especially E. coli O157:H7, Shiga toxin-producing E. coli (STEC) and Shigella. Please contact Alice Welch at Alice.Welch@fda.hhs.gov for more information.

Discovery of and Use of Fragments of DOC1 as Antiangiogenic and Antitumor Therapy

Sat, 01 Nov 2008 09:00:00 GMT

This invention describes small cDNA fragments of the coding region for wild type filamin A interacting protein 1-like (FILIP1L), previously known as down-regulated in ovarian cancer 1-like (DOC1) and variant 2 of FILIP1L genes that encode proteins that result in the inhibition of cell migration and motility, induce cell apoptosis and inhibit cell proliferation. These effects can be seen on endothelial cells and on tumor cells. These coding sequences have successfully been delivered to endothelial cells and tumor cells both in vitro and in vivo, and have demonstrated significant anti-tumor activity. In addition, the inventors have for the first time expressed the recombinant protein and developed antibodies to detect the protein fragments by Western, ELISA and immunohistochemistry. The significance of this invention is that it could provide for a series of new anti-cancer therapeutics and for the diagnostic means to follow their expression levels. CRADA Opportunity: The National Cancer Institute Hatfield Clinical Research Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Discovery of and Use of Fragments of DOC1 as Antiangiogenic and Antitumor Therapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Indoline Compounds for the Treatment of Spinal Muscular Atrophy (SMA) and Other Diseases

Sat, 01 Nov 2008 13:00:00 GMT

With the goal to treat SMA in patients, several indoline compounds were made and tested for activity. Tests in cells demonstrate that these drugs increased the levels of active SMN protein. This is encouraging since low levels of this protein appears to be the cause of neuronal death that leads to SMA. This class of compounds appears to operate via read-through of a non-sense stop-codon to produce full length, functional protein in SMA models. This mechanism may have utility in several other neurological disorders, including cystic fibroses and Duchene’s Muscular Dystrophy.

In addition, these compounds have also been shown to increase the concentration of a glutamate transporter protein in cells, which acts to recover glutamate back into neurons after release. Since the toxic effect of unrecovered excess glutamate is observed in many notorious neurological conditions, these compounds have potential for prevention or treatment. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize drugs for the treatment of SMA, as well as investigation into novel uses for these indoline compounds. Please contact Dr. Melissa Maderia at maderiam@mail.nih.gov or 301-451-3943 for more information.

Human Monoclonal Antibodies Against Yersinia pestis

Sat, 01 Nov 2008 17:00:00 GMT

The technology describes a group of three (3) human monoclonal antibodies directed against the Yersinia pestis (Y. pestis) bacterium, the etiologic pathogen of the fatal disease Plague. These antibodies are specifically directed against two of the bacterium’s virulent factors, the F1 capsid protein (one antibody) and the low-calcium response antigen V (LcrV) (two antibodies). The antibodies have been shown to provide protection against Y. pestis challenge in a mouse model, with the highest protection attained with a combination of all three. The NIH offers the subject antibodies for licensing primarily for the development of therapeutic and/or prophylactic treatment against Y. pestis infections. Additionally, the antibodies may find use in research related to the pathogenicity of Y. pestis as well as for the development of new treatment against this pathogen.

Although human plague in the United States has occurred as mostly scattered cases in rural areas (an average of 10 to 15 persons each year), and globally, according to the World Health Organization there are only 1,000 to 3,000 cases of plague every year, it is however of significant importance to develop effective treatment against the plague disease, because of its biodefense significance. Y. pestis is included in the CDC and NIH’s category A agents that can be readily used as a biological weapon in the hand of bioterrorists. CRADA Opportunity: The National Cancer Institute CCRNP, Protein Interactions Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize human monoclonal antibodies against Yersinia pestis. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Treatment and Prevention of Age-Related Macular Degeneration and Other Eye-Related Diseases

Sat, 01 Nov 2008 21:00:00 GMT

The retinal pigment epithelium (RPE) plays a significant role in regulating the microenvironment around the photoreceptors in the distal retina, where the events of phototransduction take place.

Expression profiling of microRNA (miRNAs) in RPE and the adjacent retina and choroid was used to identify six miRNAs enriched in RPE. The potential use of anti-miRNAs specifically directed against miRNA 204 and miRNA 211 to prevent epithelial cell differentiation, proliferation and migration is disclosed. The miRNA 204 and miRNA 211 play a critical role in the control transepithelial electrical resistance. This technology further describes the significance of miRNAs in regulating junctional complexes in epithelial cells.

The claims in the pending patent application are directed towards methods and compositions containing anti-miRNAs or miRNA mimics for preventing or treating detrimental epithelial cell proliferation or loss of epithelial cell differentiation. CRADA Opportunity: The National Eye Institute, Section on Epithelial and Retinal Physiology and Disease, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of RPE-specific micro RNAs or anti-miRNAs or miRNA mimics for the treatment and prevention of age-related macular degeneration (AMD) and proliferative vitreal retinopathy, and more generally for preventing or treating detrimental epithelial cell proliferation or loss of epithelial cell differentiation, e.g., in the treatment and prevention of neovascular diseases and carcinoma.. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods for Using Interferon Gamma to Absorb Fluid From the Subretinal Space

Sun, 02 Nov 2008 01:00:00 GMT

The accumulation of subretinal fluid is associated with certain adverse ocular conditions (including chronic macular edema, age related macular degeneration, and diabetic retinopathy), or retinal injury, or post-surgical complications. Often aberrant proliferation and migration of retinal pigment epithelial (RPE) cells is also associated with these ocular conditions. The RPE is a highly specialized derivative of the neuroectoderm with multiple roles in the maintenance of normal ocular function. Dysfunction of RPE cells has been implicated in inflammatory, degenerative, and dystrophic diseases of the retina and choroid. Interferon gamma (IFN gamma) has been implicated in the pathogenesis of a number of intraocular inflammatory diseases of infectious or presumed autoimmune origin. IFN gamma has been detected in vitreous aspirates of patients with uveitis, proliferative vitreoretinopathy, and idiopathic inflammatory eye diseases.

The technology provides for methods by which interferon-gamma (IFN-gamma) can be used to remove subretinal fluid. The application of INF-gamma may be by external application (e.g. eye drops or ointments) or by subretinal injection. The claims in the pending patent application are directed to methods for treating decreases in visual acuity that are associated with diseases that cause the accumulation of fluid in the subretinal space. Additional claims are directed at methods for treating age-related macular degeneration, chronic macular edema, diabetic retinopathy, retinal detachment, or glaucoma that comprise decreasing the amount of fluid present in the subretinal space of patients suffering from such disorders by administering an amount of interferon gamma to the eyes of the patients effective to decrease the amount of fluid present in the subretinal space of the patients. CRADA Opportunity: The National Eye Institute, Section on Epithelial and Retinal Physiology and Disease, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods that activate immune system mediated fluid removal from the distal retina. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Induced Internalization of Surface Receptors to Disrupt Cell Surface Signaling

Sat, 01 Nov 2008 05:00:00 GMT

Cell-surface receptors are responsible for the biological activities of many molecules. Specific ligands bind to them, causing the cell-surface receptors to internalize or bring the receptor and ligand inside the cell. A number of diseases, including cancer, metabolic disorders, and viral infections are known to require the expression of cell-surface receptors for critical pathogenetic steps. This has prompted significant research efforts towards the development of pharmaceutical agents that block the signals from cell-surface receptors. While this current research shows great promise, there is a strong need for new therapeutic strategies that utilize the mechanistic properties of cell-surface receptors.

This technology describes a strategy for artificially inducing the internalization of surface receptors, and thereby blocking the effects of the ligands associated with that receptor. This method employs bifunctional ligands that bind to both a scavenger receptor and a target receptor. As proof of concept, the inventors Drs. Narazaki and Tosato have shown that a ligand capable of binding to the scavenger receptor SREC-1 and the neuropilin-1 receptor NRP1 induces the internalization of NRP1 and inhibits NRP1 signaling. The inventors propose that this strategy can be used to inhibit signaling from any target receptor if an appropriate bifunctional ligand is used. For example, the concept could be expanded to other receptors, such as HDL and LDL receptors. Likewise the bifunctional ligand could include specific antibodies or modified ligands that recognize cell surface receptors of biological importance. Accordingly, this approach could be used to limit tumor angiogenesis, limit tumor growth, block metastasis formation, block inflammation, block viral infection, and treat just about any disease where we identify a cell surface receptor an the molecular basis for disease. CRADA Opportunity: The National Cancer Institute, Laboratory of Cellular Oncology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the technology aimed at promoting selective receptor internalization as a means to neutralize ligand function and receptor signaling. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Simple Genetic Test for Kidney Disease

Sat, 01 Nov 2008 09:00:00 GMT

This technology relates to methods of diagnosing a predisposition to diseases that cause chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Variations in a gene, non-muscle myosin IIA (MYH9), are associated with 79% of the risk of focal segmental glomerulosclerosis (FSGS), the disease that causes ESKD, in African Americans with HIV, and 56% of African Americans as a whole. The variants are also associated with a 2-3 fold increased risk for end stage kidney disease (ESKD) associated with hypertension. The variations are also present among European Americans, however they are less common.

A simple genetic screening test has been developed that identifies single nucleotide polymorphisms (SNP) and haplotypes in the non-muscle myosin gene MYH9. These variants confer genetic risk for the following kidney diseases: FSGS, collapsing glomerulopathy, HIV-associated nephropathy, hypertensive kidney disease, sickle cell nephropathy, lupus nephropathy, and possibly other kidney diseases. CRADA Opportunity: The National Cancer Institute, Laboratory of Genomic Diversity, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize genetic testing for MYH9. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Fully Human Anti-Human Monoclonal Antibody Helpful in Developing Therapies Against Autoimmune and Infectious Diseases and Cancer

Sat, 01 Nov 2008 13:00:00 GMT

Available for licensing is a fully human monoclonal antibody (KYK-2.0 IgG1) with high specificity and affinity to human NKG2D, a stimulatory or costimulatory receptor located on the cell surface of natural killer (NK) cells and CD8+ T cells. NKG2D plays a role in mediating immune responses in autoimmune and infectious diseases and cancer and it makes NKG2D an attractive target for therapeutic intervention. Nonetheless, monoclonal antibodies to NKG2D that are suitable for clinical investigations have not been available. In solution, KYK-2.0 IgG1 interferes with the cytolytic activity of human NK cells. When immobilized, KYK-2.0 IgG1 induces human NK cell activation. The dual antagonistic and agonistic activity promises a broad range of therapeutic applications. CRADA Opportunity: The Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the fully human anti-human NKG2D monoclonal antibody KYK-2.0 IgG1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Predictive Test for Age-Related Macular Degeneration in Asymptomatic Individuals

Sat, 01 Nov 2008 17:00:00 GMT

Age-related macular degeneration (ARMD) is the leading cause of severe, irreversible vision loss for those over the age of fifty in the United States and in other developed countries. Thirteen million Americans over the age of forty have ARMD. ARMD is caused by the deterioration of the central area of the retina, or macula, resulting in a loss of central vision. This disease is believed to be a multigenic disorder, and is triggered by environmental factors such as smoking, age or diet in genetically susceptible individuals.

The present invention describes a highly predictive genetic test for universal practical clinical use to identify individuals at increased risk for ARMD. It comprises a rapid, accurate and affordable genetic screen, utilizing DNA microarray technology on a single chip. Sixteen genes are screened for 90 mutations/polymorphisms associated with ARMD, with a high predictive power (up to 92.7%) to identify asymptomatic carriers at risk. Accurate prediction of genetic susceptibility to this disorder will allow interventions to protect at-risk individuals. CRADA Opportunity: The NICHD Section on Clinical Genomics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Method Evolved for Recognition and Testing of Age-Related Macular Degeneration (MERT-ARMD). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods for Accurately Measuring and Regulating Bound Adrenomedullin

Sat, 01 Nov 2008 21:00:00 GMT

This technology involves an array of applications relating to a key discovery regarding adrenomedullin-binding proteins.

Adrenomedullin (AM) is a ubiquitously-expressed peptide first found in human pheochromocytoma, a cancer of the adrenal medulla. AM appears to function as a universal autocrine growth factor, driving cell proliferation, as a vasodilator, as a mechanism for protecting cells against oxidative stress in hypoxic injury, and as a dose-dependent inhibitor of insulin secretion. Accordingly, methods for measuring in vivo levels of AM accurately, and methods for regulating the activity of available AM, may be critically important in diagnosis and treatment of many conditions, such as heart disease, pulmonary disease, liver cirrhosis, cancer, diabetes, sepsis, and inflammation.

The present technology centers on the observation that AM binds to Complement Factor H (CFH) in vivo. Without a means to determine the amount of AM that is bound to CFH, measurements of AM are inaccurate, and therapies focused on the AM-CFH complex may have advantages compared to therapies focused on AM alone.

The technology includes methods for measuring and utilizing purified AM-binding proteins, or functional portions thereof, to diagnose, treat, and monitor AM-related diseases. A second aspect includes the identification and isolation of the AM-CFH complex. Antibodies and small-molecule antagonists (which can down-regulate the function of AM, CFH, and the AM-CFH complex) have also been isolated. Collectively, the technology provides methods for diagnosis and treatment of conditions such as cancer, diabetes, or other conditions that are influenced by AM levels. CRADA Opportunity: The National Cancer Institute (NCI)/Angiogenesis Core Facility is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize AM-CFH complex involvement with tumor angiogenesis and identifying potential Rxs to disrupt this effect. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Molecular Motors Powered by Proteins

Sun, 02 Nov 2008 01:00:00 GMT

The technology available for licensing and commercial development relates to molecular motors powered by proteins. Some implementations describe a molecular motor in which multiple concentric cylinders or nested cones rotate around a common longitudinal axis. Opposing complementary surfaces of the cylinders or cones are coated with complementary motor protein pairs, such as actin and myosin. The actin and myosin interact with one another in the presence of ATP to rotate the cylinders or cones relative to one another, and this rotational energy is harnessed to produce work. Speed of movement is controlled by the concentration of ATP and the number of nested cylinders or cones. The length of the cylinders or cones can also be used to control the power generated by the motor.

Another configuration forms the motor out of a set of stacked disks, much like CDs on a spindle. The advantage of this form is extreme simplicity of construction compared to the nested cylinders or cones. In yet another configuration, which has aspects of both of the previous forms, the surfaces are broken into annular rings in order to overcome that the inner surfaces rotate at a different rate than the outer surfaces. This belt form may ultimately be used in molecular manufacturing. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Molecular Rotation Engine. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Matriptase Hypomorphic Mouse Model of a Human Ichthyosis

Wed, 01 Oct 2008 05:00:00 GMT

Available for licensing are mice with greatly reduced levels of matriptase, a membrane protease involved in epithelial development, immune function, and carcinogenesis. These mice were created to study autosomal recessive ichthyosis with hypotricosis (ARIH), an inherited human disease that has been linked to a mutation in the ST14 gene that encodes matriptase. These mice manifest the same defects seen in people afflicted by ARIH so it can be an effective model for studying the role of matriptase in disorders that affect skin development. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Oral and Pharyngeal Cancer Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D. at 301-402-0540 or bradleyda@nidcr.nih.gov for more information.

Method of Treating and Preventing Infections in Immunocompromised Subjects with Immunostimulatory CpG Oligonucleotides

Wed, 01 Oct 2008 09:00:00 GMT

Primary disorders of the immune system can be divided into four categories, (1) disorders of the humoral immunity, (2) disorders of cellular immunity, (3) disorders of phagocytes, and (4) disorders of complement. In addition, there are many causes of secondary immunodeficiency such as treatment with immunosuppressive or chemotherapeutic agents, protein-losing enteropathy, and infection with a human immunodeficiency virus (HIV). Generally, immunocompromised patients are unable to mount an immune response to a vaccine or an infection in the same manner as non-immunocompromised individuals.

Opportunistic infections to which individuals infected with HIV are susceptible include bacterial infections such as salmonellosis, syphilis and neurosyphilis, tuberculosis (TB), a typical mycobacterial infection, and bacillary angiomatosis (cat scratch disease), fungal infections such as aspergillosis, candidiasis (thrush, yeast infection), coccidioidomycosis, cryptococcal meningitis, and histoplasmosis, protozoal infections such as cryptosporidiosis, isosporiasis, microsporidiosis, Pneumocystis Carinii pneumonia (PCP), and toxoplasmosis, viral infections such as Cytomegalovirus (CMV), hepatitis, herpes simplex (HSV, genital herpes), herpes zoster (HZV, shingles), human papilloma virus (HPV, genital warts, cervical cancer), Molluscum Contagiosum, oral hairy leukoplakia (OHL), and progressive multifocal leukoencephalopathy (PML), and neoplasms such as Kaposi's sarcoma, systemic non-Hodgkin's lymphoma (NHL), and primary CNS lymphoma, among others. These opportunistic infections remain principally responsible for the morbidity and mortality associated with HIV disease.

This application claims use of immunostimulatory D-type CpG oligonucleotides for the treatment of immunocompromised individuals. More specifically, the application claims use of immunostimulatory D-type CpG oligonucleotides for the treatment of individuals infected with HIV. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Immunology, Immune Modulation Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method of Treating Infectious and Inflammatory Lung Disease with Suppressive Oligonucleotides

Wed, 01 Oct 2008 13:00:00 GMT

Lung disease is the number three killer in America, responsible for one in seven deaths, and lung disease and other breathing problems are the number one killer of babies younger than one year old. Today, more than thirty (30) million Americans are living with chronic inflammatory lung diseases such as emphysema and chronic bronchitis. In addition, approximately one hundred and fifty thousand (150,000) Americans are affected by acute respiratory distress syndrome (ARDS) each year.

Many lung diseases are associated with lung inflammation. For example, ARDS involves the rapid onset of progressive malfunction of the lungs, and is usually associated with the malfunction of other organs due to the inability to take up oxygen. The condition is associated with extensive lung inflammation and small blood vessel injury in all affected organs. ARDS is commonly precipitated by trauma, sepsis (systemic infection), diffuse pneumonia, and shock. It also may be associated with extensive surgery, and certain blood abnormalities. In many cases of ARDS and other inflammatory lung diseases, the inflammatory response that accompanies the underlying disease state is much more dangerous than the underlying infection or trauma.

This application claims use of suppressive oligonucleotides to suppress lung inflammation. More specifically, the application claims use of suppressive oligonucleotides for the treatment, prevention, or inhibition of pneumonia, ARDS, and chronic bronchitis. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Immunology, Immune Modulation Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of Suppressive Oligonucleotides to Treat Uveitis

Wed, 01 Oct 2008 17:00:00 GMT

Uveitis is a major cause of visual loss in industrialized nations. Uveitis refers to an intraocular inflammation of the uveal tract, namely, the iris, choroids, and ciliary body. Uveitis is responsible for about ten percent (10 %) of the legal blindness in the United States. Complications associated with uveitis include posterior synechia, cataracts, glaucoma and retinal edema.

Suppressive CpG oligodeoxynucleotides (ODNs) are ODNs capable of reducing an immune response, such as inflammation. Suppressive ODNs are DNA molecules of at least eight nucleotides in length, where the ODN forms a G-tetrad, and has a circular dichroism value greater than 2.9. In a suppressive ODN, the number of guanosines is at least two.

This application claims compositions and methods for the treatment of uveitis. Specifically, the application claims use of suppressive CpG ODNs to treat uveitis. The compositions and methods of the application can be used for the treatment of anterior, posterior and diffuse uveitis. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Immunology, Immune Modulation Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Monoclonal Antibodies That Bind or Neutralize Dengue Virus

Wed, 01 Oct 2008 21:00:00 GMT

Among the arthropod-borne flaviviruses, the four dengue virus serotypes, dengue type 1 virus (DENV-1), dengue type 2 virus (DENV-2), dengue type 3 virus (DENV-3), and dengue type 4 virus (DENV-4 are most important in terms of human morbidity and geographic distribution. Dengue viruses cause dengue outbreaks and major epidemics in most tropical and subtropical areas where Aedes albopictus and Aedes aegypti mosquitoes are abundant. Dengue infection produces fever, rash, and joint pain in humans. A more severe and life-threatening form of dengue, characterized by hemorrhagic fever and hemorrhagic shock, has occurred with increasing frequency in Southeast Asia and Central and South America, where all four dengue virus serotypes circulate. A safe and effective vaccine against dengue is currently not available. Passive immunization with monoclonal antibodies from non-human primates or humans represents a possible alternative to vaccines for prevention of illness caused by dengue virus.

The application claims monoclonal antibodies that bind or neutralize dengue type 1, 2, 3, and/or 4 viruses. The application also claims fragments of such antibodies retaining dengue virus-binding ability, fully human or humanized antibodies retaining dengue virus-binding ability, and pharmaceutical compositions including such antibodies. The application also claims isolated nucleic acids encoding the antibodies of the invention. Additionally, application claims prophylactic, therapeutic, and diagnostic methods employing the antibodies and nucleic acids of the invention. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Ching-Juh Lai at 301-594-2422 for more information.

Beta 1,4-Galactosyltransferases with Altered Donor and Acceptor Specificities, Compositions and Methods of Use: Development of Pharmaceuticals and Improved Vaccines

Thu, 02 Oct 2008 01:00:00 GMT

The present invention relates to the field of glycobiology, specifically to glycosyltransferases. The present invention provides structure-based design of novel glycosyltransferases and their biological applications.

The structural information of glycosyltransferases has revealed that the specificity of the sugar donor in these enzymes is determined by a few residues in the sugar-nucleotide binding pocket of the enzyme, which is conserved among the family members from different species. This conservation has made it possible to reengineer the existing glycosyltransferases with broader sugar donor specificities. Mutation of these residues generates novel glycosyltransferases that can transfer a sugar residue with a chemically reactive functional group to N-acetylglucosarnine (GlcNAc), galactose (Gal) and xylose residues of glycoproteins, glycolipids and proteoglycans (glycoconjugates). Thus, there is potential to develop mutant glycosyltransferases to produce glycoconjugates carrying sugar moieties with reactive groups that can be used in the assembly of bio-nanoparticles to develop targeted-drug delivery systems or contrast agents for medical uses.

Accordingly, methods to synthesize N-acetylglucosamine linkages have many applications in research and medicine, including in the development of pharmaceutical agents and improved vaccines that can be used to treat disease.

The invention claims beta (1,4)-galactosyltransferase I mutants having altered donor and acceptor and metal ion specificities, and methods of use thereof. In addition, the invention claims methods for synthesizing oligosaccharides using the beta (1,4)-galactosyltransferase I mutants and to using the beta (1,4)-galactosyltransferase I mutants to conjugate agents, such as therapeutic agents or diagnostic agents, to acceptor molecules. More specifically, the invention claims a double mutant beta 1, 4 galactosyltransferase, human beta-1, 4-Tyr289Leu-Met344His-Gal-T1, constructed from the individual mutants, Tyr289Leu-Gal-T1 and Met344His-Gal-T1, that transfers modified galactose in the presence of magnesium ion, in contrast to the wild-type enzyme which requires manganese ion. CRADA Opportunity: The National Cancer Institute's Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize glycosyltransferases. Please contact John D. Hewes, Ph.D., Technology Transfer Specialist, NCI, at (301) 435-3121 or hewesj@mail.nih.gov for more information.

Alpha 1-3 N-Acetylgalactosaminyltransferases with Altered Donor and Acceptor Specificities, Compositions, and Methods of Use: Development of Pharmaceutical Agents and Improved Vaccines

Wed, 01 Oct 2008 05:00:00 GMT

The present invention relates to the field of glycobiology, specifically to glycosyltransferases. The present invention provides structure-based design of novel glycosyltransferases and their biological applications.

The structural information of glycosyltransferases has revealed that the specificity of the sugar donor in these enzymes is determined by a few residues in the sugar-nucleotide binding pocket of the enzyme, which is conserved among the family members from different species. This conservation has made it possible to reengineer the existing glycosyltransferases with broader sugar donor specificities. Mutation of these residues generates novel glycosyltransferases that can transfer a sugar residue with a chemically reactive functional group to N-acetylglucosarnine (GlcNAc), galactose (Gal) and xylose residues of glycoproteins, glycolipids and proteoglycans (glycoconjugates). Thus, there is potential to develop mutant glycosyltransferases to produce glycoconjugates carrying sugar moieties with reactive groups that can be used in the assembly of bio-nanoparticles to develop targeted-drug delivery systems or contrast agents for medical uses.

Accordingly, methods to synthesize N-acetylglucosamine linkages have many applications in research and medicine, including in the development of pharmaceutical agents and improved vaccines that can be used to treat disease.

This application claims compositions and methods based on the structure-based design of alpha 1-3 N-Acetylgalactosaminyltransferase (alpha 3 GalNAc-T) mutants from alpha l-3galactosyltransferase (a3Gal-T) that can transfer 2'-modified galactose from the corresponding UDP-derivatives due to mutations that broaden the alpha 3Gal-T donor specificity and make the enzyme alpha3 GalNAc-T. CRADA Opportunity: The National Cancer Institute's Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize structure-based design of novel glycosyltransferases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of CpG Oligodeoxynucleotides to Induce Epithelial Cell Growth

Wed, 01 Oct 2008 09:00:00 GMT

Wound repair is the result of complex interactions and biologic processes. Three phases have been described in normal wound healing: acute inflammatory phase, extracellular matrix and collagen synthesis, and remodeling. The process involves the interaction of keratinocytes, fibroblasts and inflammatory cells at the wound site. The sequence of the healing process is initiated during an acute inflammatory phase with the deposition of provisional tissue. This is followed by re-epithelialization, collagen synthesis and deposition, fibroblast proliferation, and neovascularization, all of which ultimately define the remodeling phase. These events are influenced by growth factors and cytokines secreted by inflammatory cells or by the cells localized at the edges of the wound.

Tissue regeneration is believed to be controlled by specific peptide factors which regulate the migration and proliferation of cells involved in the repair process. Thus, it has been proposed that growth factors will be useful therapeutics in the treatment of wounds, burns and other skin disorders. However, there still remains a need for additional methods to accelerate wound healing and tissue repair.

This application claims methods of increasing epithelial cell growth. The methods include administering a therapeutically effective amount of a CpG oligodeoxynucleotide (ODN) to induce epithelial cell division. Also claimed are methods of inducing wound healing. The method includes treating the wound with a CpG oligonucleotide, thereby inducing wound healing. The wound can be any type of wound, including trauma or surgical wounds. The CpG ODN can be applied systemically or locally. CRADA Opportunity: The Laboratory of Experimental Immunology of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of increasing epithelial cell growth. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Live Attenuated Virus Vaccines for La Crosse Virus and Other Bunyaviridae

Wed, 01 Oct 2008 13:00:00 GMT

La Crosse virus (LACV), family Bunyaviridae, is a mosquito-borne pathogen endemic in the United States. LACV infection results in 70–130 clinical cases a year and is the major cause of pediatric arboviral encephalitis in North America. LACV was first identified as human pathogen in 1960 after its isolation from a 4 year-old girl from Minnesota who suffered meningoencephalitis and later died in La Crosse, Wisconsin. The majority of LACV infections are mild and never reported, however serologic studies estimate annual infection rates of 10–30/100,000 in endemic areas. LACV is a member of the California serogroup of viruses in the genus Orthobunyavirus. The serogroup contains members found on five continents that include human pathogens such as La Crosse, Snowshoe hare, and Jamestown Canyon viruses in North America; Guaroa virus in North and South America; Inkoo and Tahyna viruses in Europe; and Lumbo virus in Africa. Children who recover from severe La Crosse encephalitis may have significantly lower IQ scores than expected and a high prevalence (60% of those tested) of attention-deficit-hyperactivity disorder. Seizure disorders are also common in survivors. LACV can also cause encephalitis in immunosuppressed adults. Projected lifelong economic costs associated with neurologic sequelae range from $48,775–3,090,398 per case. At present, a vaccine or FDA approved antiviral therapy is not available.

This application principally claims live attenuated LACV vaccine compositions, but also includes subunit vaccine compositions including California encephalitis virus (CEV) serogroup immunogens, attenuated and inactivated CEV serogroup and chimeric Bunyaviridae. Also claimed are methods of treating or preventing CEV serogroup infection in a mammalian host, methods of producing a subunit vaccine composition, isolated polynucleotides comprising a nucleotide sequence encoding a CEV serogroup immunogen, methods for detecting LACV infection in a biological sample and infectious chimeric Bunyaviridae. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize live attenuated virus vaccine candidates for La Crosse virus and other Bunyaviridae. Please contact Dr. Whitehead at 301-496-7692 for more information.

Development of Antigenic Chimeric St. Louis Encephalitis Virus/Dengue Virus Type Four Recombinant Viruses (SLEV/DEN4) as Vaccine Candidates for the Prevention of Disease Caused by SLEV

Wed, 01 Oct 2008 17:00:00 GMT

St. Louis Encephalitis Virus (SLEV) is a mosquito-borne flavivirus that is endemic in the Americas and causes sporadic outbreaks of disease in humans. SLEV is a member of the Japanese encephalitis virus serocomplex and is closely related to West Nile Virus (WNV). St. Louis encephalitis is found throughout North, Central, and South America, and the Caribbean, but is a major public health problem mainly in the United States. Prior to the outbreak of West Nile virus in 1999, St. Louis encephalitis was the most common human disease caused by mosquitoes in the United States. Since 1964, there have been about 4,440 confirmed cases of St. Louis encephalitis, with an average of 130 cases per year. Up to 3,000 cases have been reported during epidemics in some years. Many more infections occur without symptoms and go undiagnosed. At present, a vaccine or FDA approved antiviral therapy is not available.

The inventors have previously developed a WNV/Dengue4Delta30 antigenic chimeric virus as a live attenuated virus vaccine candidate that contains the WNV premembrane and envelope (prM and E) proteins on a dengue virus type 4 (DEN4) genetic background with a thirty nucleotide deletion (Delta30) in the DEN4 3’-UTR. Using a similar strategy, the inventors have generated an antigenic chimeric virus, SLE/DEN4Delta30. Preclinical testing results indicate that chimerization of SLE with DEN4Delta30 decreased neuroinvasiveness in mice, did not affect neurovirulence in mice, and appeared to overattenuate the virus for non-human primates. Modifications of the SLE/DEN4Delta30 vaccine candidate are underway to improve its immunogenicity.

This application claims live attenuated chimeric SLE/DEN4Delta30 vaccine compositions and bivalent WNV/SLE/DEN4Delta30 vaccine compositions. Also claimed are methods of treating or preventing SLEV infection in a mammalian host, methods of producing a subunit vaccine composition, isolated polynucleotides comprising a nucleotide sequence encoding a SLEV immunogen, methods for detecting SLEV infection in a biological sample and infectious chimeric SLEV. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize live attenuated virus vaccine candidates for St. Louis encephalitis virus. Please contact Dr. Whitehead at 301-496-7692 for more information.

Monoclonal Antibodies Against Orthopoxviruses

Wed, 01 Oct 2008 21:00:00 GMT

Concerns that variola (smallpox) virus might be used as a biological weapon have led to the recommendation of widespread vaccination with vaccinia virus. While vaccination is generally safe and effective for prevention of smallpox, it is well documented that various adverse reactions in individuals have been caused by vaccination with existing licensed vaccines. Vaccinia immune globulin (VIG) prepared from vaccinated humans has historically been used to treat adverse reactions arising from vaccinia immunization. However, VIG lots may have different potencies and carry the potential to transmit other viral agents.

Chimpanzee Fabs against the B5 and A33 outer extracellular membrane proteins of vaccinia virus were isolated and converted into complete mAbs with human gamma1 heavy chain constant regions. The two mAbs displayed high binding affinities to B5 and A33. The mAbs inhibited the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro, protected mice from subsequent intranasal challenge with virulent vaccinia virus, protected mice when administered 2 days after challenge, and provided significantly greater protection than that afforded by VIG. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Chimpanzee/human neutralizing monoclonal antibodies against orthopoxviruses. Please contact Dr. Robert Purcell at 301-496 5090 for more information.

Methods of Glycosylation and Bioconjugation

Thu, 02 Oct 2008 01:00:00 GMT

Eukaryotic cells express several classes of oligosaccharides attached to proteins or lipids. Animal glycans can be N-linked via beta-GlcNAc to Asn (N-glycans), O-linked via -GalNAc to Ser/Thr (O-glycans), or can connect the carboxyl end of a protein to a phosphatidylinositol unit (GPI-anchors) via a common core glycan structure. Beta (1,4)-galactosyltransferase I catalyzes the transfer of galactose from the donor, UDP-galactose, to an acceptor, N-acetylglucosamine, to form a galactose-beta (1,4)-N-acetylglucosamine bond, and allows galactose to be linked to an N-acetylglucosamine that may itself be linked to a variety of other molecules. Examples of these molecules include other sugars and proteins. The reaction can be used to make many types of molecules having great biological significance. For example, galactose-beta (1,4)-N-acetylglucosamine linkages are important for many recognition events that control how cells interact with each other in the body, and how cells interact with pathogens. In addition, numerous other linkages of this type are also very important for cellular recognition and binding events as well as cellular interactions with pathogens, such as viruses. Therefore, methods to synthesize these types of bonds have many applications in research and medicine to develop pharmaceutical agents and improved vaccines that can be used to treat disease.

The invention provides in vitro folding method for a polypeptidyl-alpha-N-acetylgalactosaminyltransferase (pp-GalNAc-T) that transfers GalNAc to Ser/Thr residue on a protein. The application claims that this in vitro-folded recombinant ppGalNAc-T enzyme transfers modified sugar with a chemical handle to a specific site in the designed C-terminal polypeptide tag fused to a protein. The invention provides methods for engineering a glycoprotein from a biological substrate, and methods for glycosylating a biological substrate for use in glycoconjugation. Also included in the invention are diagnostic and therapeutic uses. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Development of Dengue Virus Type 3 Vaccine Candidates

Wed, 01 Oct 2008 05:00:00 GMT

The disease burden associated with dengue virus infection has increased over the past several decades in the tropical and semi-tropical regions of the world, where over 2 billion people live at risk of dengue infection. Annually, there are an estimated fifty (50) to one hundred (100) million cases of dengue fever, making development of an effective vaccine a priority. In addition, there is a need for a "travelers vaccine" to protect those visiting dengue virus endemic areas, similar in scope to other currently available "travelers vaccines", such as hepatitis A vaccine.

The previously identified delta30 attenuating mutation, created in each dengue virus serotype by the removal of 30 homologous nucleotides from the 3'-UTR, is capable of attenuating wild-type strains of dengue virus type 1 (DEN1), type 4 (DEN4) and to a limited extent type 2 (DEN2). These DEN1delta30 and DEN4delta30 viruses have been shown to be both safe and immunogenic in humans. However, the delta30 mutation failed to have an attenuating effect on dengue virus type 3 (DEN3). To generate DEN3 vaccine candidates with a clearly attenuated phenotype, viruses were produced containing 3'-UTR deletions consisting of extensions of the original delta30 mutation or additional mutations which remove stem-loop structures similar to those removed by delta30. In addition, the entire 3'-UTR of DEN3 was replaced with the 3'-UTR derived from DEN4 and containing the delta30 mutation. Studies in monkeys demonstrated that these newly developed viruses are highly attenuated, yet sufficiently immunogenic to warrant their further development for use as live attenuated vaccine candidates. Such viruses are anticipated to become the DEN3 component of a tetravalent vaccine formulation designed to immunize against all four dengue virus serotypes. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or bm25f@nih.gov for more information.

Catalytic Domains of [beta](1,4)-galactosyltransferase I Having Altered Donor and Acceptor Specificities, Domains That Promote In Vitro Protein Folding, and Methods for Their Use

Wed, 01 Oct 2008 09:00:00 GMT

[beta](1,4)-galactosyltransferase I catalyzes the transfer of galactose from the donor, UDP-galactose, to an acceptor, N-acetylglucosamine, to form a galactose-[beta](1,4)-N-acetylglucosamine bond. This reaction allows galactose to be linked to an N-acetylglucosamine that may itself be linked to a variety of other molecules. The reaction can be used to make many types of molecules having great biological significance. For example, galactose-[beta](1,4)-N-acetylglucosamine linkages are very important for cellular recognition and binding events as well as cellular interactions with pathogens, such as viruses. Therefore, methods to synthesize these types of bonds have many applications in research and medicine to develop pharmaceutical agents and improved vaccines that can be used to treat disease.

The present invention is based on the surprising discovery that the enzymatic activity of [beta](1,4)-galactosyltransferase can be altered such that the enzyme can make chemical bonds that are very difficult to make by other methods. These alterations involve mutating the enzyme such that the mutated enzyme can transfer many different types of sugars from sugar nucleotide donors to many different types of acceptors. Therefore, the mutated [beta](1,4)-galactosyltransferases of the invention can be used to synthesize a variety of products that, until now, have been very difficult and expensive to produce.

The invention also provides amino acid segments that promote the proper folding of a galactosyltransferase catalytic domain and mutations in the catalytic domain that enhance folding efficiency and make the enzyme stable at room temperature. The amino acid segments may be used to properly fold the galactosyltransferase catalytic domains of the invention and thereby increase their activity. The amino acid segments may also be used to increase the activity of galactosyltransferases that are produced recombinantly. Accordingly, use of the amino acid segments according to the invention allows for production of [beta](1,4)-galactosyltransferases having increased enzymatic activity relative to [beta](1,4)-galactosyltransferases produced in the absence of the amino acid segments. CRADA Opportunity: The National Cancer Institute's Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of galactose and modified galactose to be linked to an N-acetylglucosamine that may itself be linked to a variety of other molecules. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Dengue Tetravalent Vaccine Containing a Common 30 Nucleotide Deletion in the 3'-UTR of Dengue Types 1, 2, 3, and 4

Wed, 01 Oct 2008 13:00:00 GMT

The invention relates to a dengue virus tetravalent vaccine containing a common 30-nucleotide deletion (delta30) in the 3'-untranslated region (UTR) of the genome of dengue virus serotypes 1, 2, 3, and 4. The previously identified delta30 attenuating mutation, created in dengue virus type 4 (DEN4) by the removal of 30 nucleotides from the 3'-UTR, is also capable of attenuating a wild-type strain of dengue virus type 1 (DEN1). Removal of 30 nucleotides from the DEN1 3'-UTR in a highly conserved region homologous to the DEN4 region encompassing the delta30 mutation yielded a recombinant virus attenuated in rhesus monkeys to a level similar to recombinant virus DEN4delta30. This established the transportability of the delta30 mutation and its attenuation phenotype to a dengue virus type other than DEN4. The effective transferability of the delta30 mutation establishes the usefulness of the delta30 mutation to attenuate and improve the safety of commercializable dengue virus vaccines of any serotype.

A tetravalent dengue virus vaccine containing dengue virus types 1, 2, 3, and 4 each attenuated by the delta30 mutation is being developed. The presence of the delta30 attenuating mutation in each virus component precludes the reversion to a wild-type virus by intertypic recombination. In addition, because of the inherent genetic stability of deletion mutations, the delta30 mutation represents an excellent alternative for use as a common mutation shared among each component of a tetravalent vaccine. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or bm25f@nih.gov for more information.

Live Attenuated Vaccine to Prevent Disease Caused by West Nile Virus

Wed, 01 Oct 2008 17:00:00 GMT

WNV has recently emerged in the U.S. and is considered a significant emerging disease that has embedded itself over a considerable region of the U.S. WNV infections have been recorded in humans as well as in different animals. To date, WNV has killed 294 people in the U.S. and caused severe disease in more than 4222 others. This project is part of NIAID’s comprehensive emerging infectious disease program, which supports research on bacterial, viral, and other types of disease-causing microbes.

The methods and compositions of this invention provide a means for prevention of WNV infection by immunization with attenuated, immunogenic viral vaccines against WNV. The invention involves a chimeric virus form consisting of parts of WNV and Dengue virus. Construction of the hybrids and their properties are described in detail in AG Pletnev et al., PNAS 2002;99(5):3036-3041.

The WNV chimeric vaccine does not target the central nervous system, which would be the case in an infection with wild type WNV. The vaccine stimulates strong anti-WNV immune responses, even following a single dose of the vaccine. When injected into mice, the vaccine protected all of the immunized animals from subsequent exposure to the New York WNV strain. The vaccine was also effective in primates. Researchers intend to begin human trials in late 2003.

The WNV vaccine may be used to protect the human population, particularly the elderly people, and domestic animals from WNV infection in the affected regions of the U.S. as well as worldwide. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, and commercialize this technology. Please contact Percy Pan at 301-451-3523 or panp@niaid.nih.gov for more information.

Development of Mutations Useful for Attenuating Dengue Viruses and Chimeric Dengue Viruses

Wed, 01 Oct 2008 21:00:00 GMT

Although flaviviruses cause a great deal of human suffering and economic loss, there is a shortage of effective vaccines. This invention relates to dengue virus mutations that may contribute to the development of improved dengue vaccines. Site directed and random mutagenesis techniques were used to introduce mutations into the dengue virus genome and to assemble a collection of useful mutations for incorporation in recombinant live attenuated dengue virus vaccines. The resulting mutant viruses were screened for several valuable phenotypes, including temperature sensitivity in Vero cells or human liver cells, host cell restriction in mosquito cells or human liver cells, host cell adaptation for improved replication in Vero cells, and attenuation in mice or in mosquitoes. The genetic basis for each observed phenotype was determined by direct sequence analysis of the genome of the mutant virus. Mutations identified through these sequencing efforts have been further evaluated by re-introduction of the identified mutations, singly, or in combination, into recombinant dengue virus and characterization of the resulting recombinant virus for phenotypes. In this manner, a menu of attenuating and growth promoting mutations was developed that is useful in fine-tuning the attenuation and growth characteristics of dengue virus vaccine candidates. The mutations promoting growth in Vero cells have usefulness for the production of live or inactivated dengue virus vaccines. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or bm25f@nih.gov for more information.

Modified Sugar Substrates and Methods of Use

Tue, 02 Sep 2008 01:00:00 GMT

Glycans can be classified as linear or branched sugars. The linear sugars are the glycosaminoglycans comprising polymers of sulfated disaccharide repeat units that are O-linked to a core protein, forming a proteoglycan aggregate. The branched glycans are found as N-linked and O-linked sugars on glycoproteins or on glycolipids. These carbohydrate moieties of the linear and branched glycans are synthesized by a super family of enzymes, the glycosyltransferases (GTs), which transfer a sugar moiety from a sugar donor to an acceptor molecule. Although GTs catalyze chemically similar reactions in which a monosaccharide is transferred from an activated derivative, such as a UDP-sugar, to an acceptor, very few GTs bear similarity in primary structure.

Eukaryotic cells express several classes of oligosaccharides attached to proteins or lipids. Animal glycans can be N-linked via beta-GlcNAc to Asparagine (N-glycans), O-linked via UDP-GalNAc to Serine/Threonine (O-glycans), or can connect the carboxyl end of a protein to a phosphatidylinositol unit (GPI-anchors) via a common core glycan structure. Thus, there is potential to develop carbohydrate substrates comprising bioactive agents that can be used to produce glycoconjugates carrying sugar moieties with bioactive agents. Such glycoconjugates have many therapeutic and diagnostic uses, e.g. in labeling or targeted delivery. Further, such glycoconjugates can be used in the assembly of bio-nanoparticles to develop targeted-drug delivery systems or contrast agents for medical uses.

This application claims methods and compositions for making and using functionalized sugars. Also claimed in the application are methods for forming a wide variety of products at a cell or in an in vitro environment. More specifically, the claimed compositions of the invention comprise a sugar nucleotide and one or more functional groups. CRADA Opportunity: The National Cancer Institute’s Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the synthesis of UDP derivatives of C2 modified galactose for use as donor substrates for glycosyltransferases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or < a href="mailto:hewesj@mail.nih.gov">hewesj@mail.nih.gov for more information.

A Novel Treatment for Malarial Infections

Mon, 01 Sep 2008 05:00:00 GMT

The inventions described herein are antimalarial small molecule inhibitors of the plasmodial surface anion channel (PSAC), an essential nutrient acquisition ion channel expressed on human erythrocytes infected with malaria parasites. These inhibitors were discovered by high-throughput screening of chemical libraries and analysis of their ability to kill malaria parasites in culture. Two separate classes of inhibitors were found to work synergistically in combination against PSAC and killed malaria cultures at markedly lower concentrations than separately. These inhibitors have high affinity and specificity for PSAC and have acceptable cytotoxicity profiles. Preliminary in vivo testing of these compounds in a mouse malaria model is currently ongoing. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antimalarial drugs that target PSAC or other parasite-specific transporters. Please contact Dana Hsu at 301-496-2644 for more information.

Human-Bovine Chimeric Respiratory Syncytial Virus (RSV) Vaccines

Mon, 01 Sep 2008 09:00:00 GMT

Available for licensing and commercial development is a patent estate and related biological materials for making human-bovine chimeric virus particles for formulating live attenuated vaccines against human respiratory syncytial virus (RSV). Chimeric human-bovine RSVs are recombinantly engineered to incorporate nucleotide sequences from both human and bovine RSV strains and produce infectious, chimeric viruses that elicit anti-RSV immunological responses in humans and non-human primates. The chimeras incorporate partial or complete human or bovine RSV background genomes with one or more recombinantly integrated heterologous genes or genome segments of a different RSV strain.

Heterologous genes of interest for making chimeric recombinants include NS1, NS2, N, P, M, SH glycoprotein (or an immunogenic domain or epitope thereof), M2(ORF1), M2(ORF2), L, F or G genes or a genome segment including a protein or portion thereof or alternatively a leader, trailer or intergenic region of the RSV genome, or a segment thereof. A variety of additional mutations and nucleotide modifications are provided within the human-bovine chimeric RSV of the invention to yield desired phenotypic and structural effects. Exemplary human-bovine chimeric RSV of the invention incorporate a chimeric RSV genome or antigenome comprising both human and bovine polynucleotide sequences, as well as a major nucleocapsid (N) protein, a nucleocapsid phosphoprotein (P), a large polymerase protein (L), and a RNA polymerase elongation factor. Additional RSV proteins may be included in various combinations to provide a range of infectious subviral particles up to a complete viral particle or a viral particle containing supernumerary proteins, antigenic determinants or other additional components. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize attenuated live vaccines against respiratory syncytial virus (RSV). Please contact Barry Buchbinder at 301-594-1696 for more information.

Respiratory Syncytial Virus (RSV) Vaccines Based on Promoter-Proximate Attenuation

Mon, 01 Sep 2008 13:00:00 GMT

Available for licensing and commercial development is a patent estate and related biological materials for producing therapeutic or prophylactic vaccines against Respiratory Syncytial Virus (RSV). The claimed vaccine strategy relates to the engineering and creation of live-attenuated RSV vaccine candidates by shifting the position of one or more viral genes relative to the viral promoter (aka promoter-proximal attenuation). The gene shifts can be constructed by insertion, deletion or rearrangement of genes or genome segments within the recombinant genome or antigenome. Viral replication can increase or decrease depending on the position of expressed viral gene and depending on the nature and degree of the positional shift. Viral gene rearrangements are selected to maintain sufficient non-infectious replication of RSV while eliciting host anti-RSV immune responses. Viral genes targeted for such rearrangement include any of the NS1, NS2, N, P, M, SH, M2(ORF1), M2(ORF2), L, F or G genes or genome segment.

One modification of particular interest is the placement of the G and F protective antigen genes in a promoter-proximal position for increased expression. The gene position-shifted RSV can be further manipulated by the addition of specific nucleotide and amino acid point mutations or host range restriction determinants to yield desired phenotypic and structural effects. CRADA Opportunity: The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize live attenuated vaccines. Please contact Michael Piziali at 301-451-3527 for more information.

Active Guidewire Visualization Device and System for MRI Guided Interventions

Mon, 01 Sep 2008 17:00:00 GMT

Available for licensing and commercial development is a guidewire device and system for MRI guidance of vascular interventions. The guidewire design, and its coupled system, enables interventionalists to visualize the location of the tip and distal shaft of an MRI compatible guidewire relative to the vascular system and surrounding anatomy. Visualization of both the shaft and tip enables interventionalists to advance the guidewire through tortuous vessels reducing the risk of puncturing vessel walls and also steering it through labyrinthine vasculature. The guidewire provided by the present invention includes distal and proximal ends with a space therein, a dipole antenna disposed in the space reserved within the guidewire body, the dipole antenna being adapted to be electrically connected to a signal processing system through a first signal channel through the proximal end of the guidewire body, and a loop antenna disposed in the space reserved within the guidewire body toward the distal end of the guidewire body, the loop antenna being adapted to be electrically connected to the signal processing system through a second signal channel through the proximal end of the guidewire body. The dipole antenna and the loop antenna are each constructed to receive magnetic resonance imaging signals independently of each other and to transmit received signals through the first and second signal channels, respectively, to be received by the signal processing system. More specifically, both loop and dipole antenna are tuned to resonate at the same Larmour frequency as produced by the magnet. CRADA Opportunity: The National Institutes of Health / Cardiac Catheter Core Lab is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Active two channel 0.035" guidewire. Please contact Ozgur Kocaturk at 301-402-9430 or kocaturko@nhlbi.nih.gov.

Microfabricated Particles Useful as MRI Contrast Agents

Mon, 01 Sep 2008 21:00:00 GMT

MRI contrast agents are versatile yet lack the sensitivity and multiplexing capabilities of optical agents. Available for licensing is an invention pertaining to microfabricated structures that can be used as MRI contrast agents with enhanced functionality or as micro-RFID (radio-frequency identification) tags. The microstructures can be engineered to appear as different effective colors when resolved using MRI as opposed to strictly grey-scale contrast of existing MRI agents. In this way they can be thought as radio-frequency analogs to quantum dots. A set of agents could be produced that would enable in vivo labeling and tracking of multiple different types of cells simultaneously. The agents can also act as radio-frequency probes of various physiological conditions. The invention can include a plurality of microstructures dispersed a liquid. The structures can have magnetic portions that vary in size, thickness and shape that are arranged to provide a substantially uniform Larmor precession frequency or a characteristic substantially uniform shift in Larmor precession frequency experienced by nuclear magnetic moments of a material when it is located in the substantially uniform field region created by the magnetic portions. In some embodiments, each of the nuclear magnetic resonance microstructures has a maximum dimension less than about 1 mm. The magnetic portions of the microstructure can be arranged proximate to each other, in contact with each other or be partially, substantially or totally coincident. CRADA Opportunity: NINDS Laboratory of Functional and Molecular Imaging is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of microfabricated devices as MRI contrast agents. Please contact Dr. Melissa Maderia at 301-451-3943 or maderiam@mail.nih.gov for more information.

A Novel Recombinant Immunotoxin SS1P (anti-mesothelin dsFv-PE38): A Therapeutic Treatment for Lung Cancer and Other Mesothelin Expressing Cancers

Tue, 02 Sep 2008 01:00:00 GMT

Mesothelin is a cell surface glycoprotein whose expression is largely restricted to mesothelial cells in normal tissues. Significantly, mesothelin is also highly expressed in many cancers (including malignant mesothelioma, ovarian cancer, lung cancer, pancreatic carcinomas, gastric carcinomas, etc.). As a result, mesothelin is an excellent target for immunotherapy.

NIH inventors have generated high affinity antibodies to mesothelin (SS1) and fused them to various functional fragments of Pseudomonas Exotoxin A (PE) to produce the immunotoxin SSIP. New SS1P constructs include PE fragments and mutants with reduced immunogenicity, resulting in immunotoxins with greater efficacy. SS1P activity was previously shown in patients suffering from mesothelioma and ovarian cancer; laboratory studies now demonstrate cytotoxicity against lung carcinoma cells. Additionally, SS1P has shown synergy with front line cancer therapeutics in a mouse model, making SS1P an excellent candidate both a stand-alone therapeutic and a combination therapeutic. CRADA Opportunity: The National Cancer Institute Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop immunotoxin SS1P. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Automated Method for Rapid Detection of Sickle Cell Disease Inhibitors

Mon, 01 Sep 2008 05:00:00 GMT

Available for licensing is a rapid and automated method for discovering potential drugs for the treatment of sickle cell anemia by determining the sickling times for a large population of red blood cells. The method uses a combination of laser photolysis and statistical processing of digital images. Sickle cell disease is an inherited disorder that affects over 70,000 Americans. The disease is characterized by presence of mutant hemoglobin S in red blood cells, which polymerizes to form fibers when deoxygenated. Such fibers lead to distortion of red blood cells into the shape of a sickle and alter the mechanical properties of these cells. Studies demonstrate that the time to polymerization involves a delay time and rapid growth phase and is particularly sensitive to hemoglobin concentration. As a result, identification of drugs that inhibit sickle cell disease is accomplished using an assay for delay times for populations of red blood cells. The invention creates a uniform time at which polymerization is initiated for all red blood cells in the sample region and accurately determines the time at which cellular distortion begins for each cell. Potential drugs are those compounds that significantly increase the delay time of sickling time, i.e. the time at which the cell changes shape due to intracellular polymerization. CRADA Opportunity: The NIDDK Laboratory of Chemical Physics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Rochelle S. Blaustein, J.D. at 301-451-3636 or rochelle.blaustein@nih.gov more information.

Use of Razoxane for the Treatment of Alzheimer's Disease

Mon, 01 Sep 2008 09:00:00 GMT

Abnormalities in the metabolism of the transition metals, iron and copper, have been demonstrated to play a crucial role in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Excessive iron accumulation in the brain occurs in both AD and PD. High levels of reactive iron can increase oxidative stress-induced neuronal vulnerability, increase the toxicity of environmental or endogenous toxins, and accelerate hallmark pathologies of these diseases.

As an example among many, the expression level of amyloid-beta precursor protein (APP) that generates the AD neurotoxic peptide, amyloid-beta (A-beta), is regulated in large part by iron levels. APP mRNA has an iron response element (IRE) in its 5'-untranslated region, and cleavage of APP to release different amyloidogenic and non-amyloidogenic peptide forms involves metalloproteases.

Elevated A-beta levels as well as plaques formed by aggregation of A-beta involve iron, and play a significant role in degeneration of the brain seen in AD. Chelators can reduce both the generation and aggregation of A-beta. Razoxane, a bisdioxopiperazine, is an orally active metal chelator approved for the treatment of cancer, where it and dexrazoxane have been effectively used for decades. In neuronal cell culture models, razoxane induced dose-dependent reductions in APP and A-beta levels without toxicity. In animal experiments (transgenic mice expressing human A-beta), razoxane substantially reduced A-beta 1-40 and 1-42 in brain by up to 46% without toxicity following once daily, 21 day administration.

The claimed invention is the novel use of razoxane and other bisdioxopiperazines to reduce amyloid-beta peptide levels, reduce aggregation of alpha-synuclein and tau protein, and reduce abnormal protein folding or aggregation for the treatment of AD and related diseases with protein aggregation pathology. Since razoxane has been approved for humans use, it could be more quickly developed as a treatment for AD, PD and other diseases. CRADA Opportunity: The National Institute on Aging, Laboratory of Neurosciences, Section on Drug Design & Development, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize razoxane and analogues for the treatment of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Please contact Nigel H. Greig (greign@grc.nia.nih.gov) for more information.

Quantitative Immunoassays for Measurement of Topoisomerase I as a Pharmacodynamic Marker for the Effect of Anti-Cancer Drugs

Mon, 01 Sep 2008 13:00:00 GMT

Topoisomerase I (TopoI) is an enzyme that catalyses DNA unwinding which is necessary for many cellular functions. Recent data from the Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS) trial demonstrates that nuclear staining of TopoI correlates with chemotherapy efficacy [J Clin Oncol (2008) 26, 2690-8]. This enzyme covalently binds with the DNA substrate and introduces a single strand break. Some anti-cancer drugs, including those in clinical trials target this cleavage site and prevent re-ligation of the unwound DNA, trapping the TopoI/DNA covalent complex. TopoI trapped by Topo I inhibitor compounds such as Topotecan is degraded by the ubiquitin/proteosome pathway. This change in intracellular TopoI levels makes total TopoI and the TopoI/DNA covalent complex potential pharmacodynamic biomarkers for monitoring TopoI inhibiting agents, used in cancer therapy.

The technology involves a validated, enzyme linked immunosorbent assay (ELISA) with a chemiluminescence readout, using commercially available antibodies to quantitate total TopoI from cell and tumor extracts.

This technology has been used in a high throughput assay for measurement of estrogen and estrogen metabolites in serum. A similar ELISA assay has also been used in NCI Phase 0 and Phase I clinical trials of a PARP inhibitor. CRADA Opportunity: The National Cancer Institute's Laboratory of Human Toxicology and Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Quantitative Immunoassays for Measurement of Topoisomerase I as a Pharmacodynamic Marker for the Effect of Anti-Cancer Drugs. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Small Molecule Inhibitors of c-Met

Mon, 01 Sep 2008 17:00:00 GMT

Aberrant c Met signaling is documented in a wide variety of malignancies and occurs via several mechanisms including amplification of c-Met (increased gene copy number), point mutations in the gene encoding c-Met, receptor over expression, and ligand dependent autocrine/paracrine receptor activation. This application describes novel small molecule inhibitors of c-Met signaling. The small molecules selectively bind to c-Met and have an IC50 in the micromolar range. The small molecules belong to two different families. One family of small molecules reduces the level of c Met expression via receptor down-regulation and blocks ATP binding. The other family of small molecules block ATP binding without inducing receptor down-regulation. Evidence suggests that the second family of compounds bind to both active and inactive conformations of c-Met. CRADA Opportunity: The National Cancer Institute, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize small molecule inhibitors of the HGF/c-Met signaling pathway. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Over-expression and Mutation of a Tyrosine Kinase Receptor FGFR4 in Tumors

Mon, 01 Sep 2008 21:00:00 GMT

Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. Most children (>70%) with the disease die at higher stage (metastatic disease).

Researchers at NIH have identified mutations in fibroblast growth factor receptor 4 (FGFR4) that are associated with RMS tumors. It is proposed that individuals with FGFR4 mutations may have an increased risk for tumor metastasis. The identified FGFR4 variants can be used to identify individuals who may benefit most from treatment with an FGFR4 inhibitor as an adjuvant to standard anticancer therapeutics to decrease the risk of tumor metastasis.

Available for licensing are methods for identifying candidates for treatment with an inhibitor of FGFR4 by determining the presence of at least one FGFR4 variant, kits for identifying said candidates, and methods for identifying compounds that induce tumor cell death or that inhibit tumor growth or metastasis. CRADA Opportunity: The National Cancer Institute, Pediatric Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Over-expression and Mutation of a Tyrosine Kinase Receptor FGFR4 in Tumors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Magnetic Resonance Imaging Methods and Systems for Estimating Cone of Uncertainty

Tue, 02 Sep 2008 01:00:00 GMT

In diffusion tensor MRI imaging it is desirable to determine and display the fiber tract dispersion, e.g., the eigenvectors and the associated uncertainties. For example, the unit eigenvector may be displayed with a cone of uncertainty around its tip. This conveys the notion that the direction of fiber is not known precisely. However, the known methods are directed to computation and visualization of a circular cone of uncertainty. These methods are suitable for practical computation and visualization of an elliptical cone of uncertainty. The current invention overcomes this problem by providing (1) a reconstruction procedure to construct the covariance matrix of a major eigenvector for each voxel of a region of interest of a subject, (2) a visualization technique to visualize the elliptical cone of uncertainty of the eigenvector, and (3) two reconstruction procedures to compute the normalized areal and circumferential measures of the elliptical cone of uncertainty. The methods can be used to diagnose medical disorders associated with anomalous changes in water diffusion. The methods can also be used in applications in material science and earth science (geomagnetism). CRADA Opportunity: The NICHD, Section on Tissue Biophysics and Biomimetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Alan E. Hubbs, Ph.D. at 301-594-4263 or hubbsa@mail.nih.gov for more information.

Botulinum Toxoid

Mon, 01 Sep 2008 05:00:00 GMT

Vaccination is the only approach that can be used to prevent botulism. A pentavalent botulinum toxoid comprised of formalin-detoxified botulinum neurotoxin (BoNT) BoNT/A, B, C, D and E hemagglutinin (Hmg) complexes has been used to immunize laboratory and military personnel since 1961, but this has never been licensed by the United States Food and Drug Administration (FDA). Vaccination immediately after toxin exposure has no protective benefit because the immune response is relatively slow compared to the rate of intoxication. The only treatment that is available upon intoxication is antibody therapy, which entails the injection of equine-derived botulinum antitoxin (BAT) or human-derived botulinum immunoglobulin (BIG) to remove toxin from the blood. Antibody therapy does not alleviate symptoms of botulism, but can limit the amount of toxin that enters nerve terminals and thus may lessen the severity and shorten the duration of paralysis.

Since a vaccine can be used to either protect a human population or produce a BAT or BIG product, it is important to have reliable methods to evaluate the antigenic integrity of botulinum vaccines. An in vitro assay that can serve in this capacity would be useful for evaluating the consistency of the antigen throughout the manufacturing process, as well as generating data that may reduce in vivo testing.

Available for licensing are a variety of new toxoids useful as botulinum vaccine antigens, for BAT or BIG production, or for development of tests to evaluate antigenicity of botulinum vaccines. The toxoids of the invention are derived from the Serotype A and B 150 kDa neurotoxin proteins. The resulting toxoids are antigenically identical to the native toxin as measured by inhibition ELISA in spite of showing a reduction of toxicity by more than 100,000-fold. Sandwich ELISA analysis indicated that the featured toxoids were two to three-fold less antigenic than the native neurotoxin compared to commercially available toxoids, which were about 100-fold less antigenic.

Preclinical studies have been performed using the toxoids of the invention. Mice were immunized twice, on Day Zero (0) and Day Fourteen (14). By Day Twenty-Eight (28), relatively high toxin-specific IgG titers were detected in animals that had received any of the in-house toxoids, with greater than 99% being IgG1 and the remainder IgG2. These immunized mice remained asymptomatic after being challenged with Fifty (50) to One Million (1,000,000) median lethal dose (LD50) units of the 900 kDa neurotoxin. In contrast, animals immunized with several different batches of commercially available toxoids did not develop measurable toxin-specific antibody titers; however, these mice did survive neurotoxin challenges with Two (2) LD50 units, but died when challenged with Six (6) LD50 units.

This application claims the formalin-detoxified botulinum compositions described above and an in vitro method for characterizing the toxoids. Also claimed are methods of making the botulinum compositions, and methods of producing antitoxin to botulinum toxin. CRADA Opportunity: The FDA Center for Biologics Evaluation and Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize botulinum toxoids. Please contact Alice Welch, Ph.D. at 301-827-0359 or Alice.Welch@fda.hhs.gov for more information.

Monodisperse and Modified Yersinia pestis Capsular F1-V Antigen Fusion Proteins for Vaccination Against Bubonic and Pneumonic Plague

Mon, 01 Sep 2008 09:00:00 GMT

An effective plague vaccine against Yersinia pestis is currently unavailable in the US. The F1-V (fusion of two Y. pestis proteins, the Fraction 1 capsular antigen and a second immunogen called the V-antigen) vaccine of this invention is a monodispersed, mutated form of F1-V fusion protein. This is a promising candidate for commercialization.

Features and benefits include:

The vaccine is substantially monomeric but does not tend to self-associate and form aggregates.
The antigen fusion proteins retain immunogenicity.
The associated, new manufacturing process provides an inexpensive means of making an effective vaccine.
The method eliminates the need for mixing components that is the case with competitive technology.

CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this plague vaccine. Please contact Marguerite J Miller at 301-435-8619 /or millermarg@niaid.nih.gov for more information.

A Rapid Ultrasensitive Assay for Detecting Prions Based on the Seeded Polymerization of Recombinant Normal Prion Protein (rPrP-sen)

Mon, 01 Sep 2008 13:00:00 GMT

Prion diseases are neurodegenerative diseases of great public concern because humans may be infected from hoofed animals used as food, food products such as milk, or blood products. Currently available tests for disease-causing prions are either incapable of detecting low concentrations of prions and must be used post-mortem or are incapable of detecting low concentrations of prions economically or accurately. This technology enables rapid and economical detection of sub-lethal concentrations of prions by using recombinant, normal, prion protein (rPrP-sen) as a marker or indicator of infectious prions in a sample. Specifically, prions (contained in a sample) seed the polymerization of rPrP-sen, and polymerized rPrP-sen is detected as an amplified indicator of prions in the sample. This assay differs from the protein-misfolding cyclic amplification assay (PMCA) because it enables the effective use of rPrP-sen and does not require multiple amplification cycles unless a higher degree of sensitivity is required. It is anticipated that this technology can be combined with additional prion-detection technologies to further improve the sensitivity of the assay. In its current embodiment, this assay has been used to detect prions in brain tissue or cerebral spinal fluid (CSF) from humans (variant CJD), sheep (scrapie), and hamsters (scrapie). CRADA Opportunity: The NIAID Laboratory of Persistent Viral Diseases, TSE/Prion Biochemistry Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Rosemary Walsh at 301-451-3528 or rcwalsh@niaid.nih.gov.

Immunogenic Peptides Against Influenza Virus

Mon, 01 Sep 2008 17:00:00 GMT

The invention described herein are peptides and polypeptides derived from the HA, NA, PB2, PB1, PA, M1, M2, NP, NS1, and NS2 proteins of influenza virus that elicit immunogenic responses; particularly neutralizing antibodies, against human and avian influenza strains H1N1, H3N2, H5N1 and H7N7. Materials in the form of immunogenic compositions including these peptides and polypeptides can also be in-licensed along with the patent rights. Pharmaceutical compositions including these peptides and polypeptides with or without adjuvants are within the scope of the invention. The inventors are currently investigating the vaccine potential of specific peptides and polypeptides. CRADA Opportunity: The FDA, Center for Biologics Evaluation and Research (CBER), Division of Viral Products, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these peptides as vaccine candidates or diagnostics. Please contact Alice Welch at alice.welch@fda.hhs.gov or 301-827-0359 for more information.

Bifunctional Compounds that Bind to Hormone Receptors

Mon, 01 Sep 2008 21:00:00 GMT

The development and progression of prostate cancer is dependent on the androgen receptor (AR), a ligand-dependent transcription factor. In the inactive form AR resides in the cytosolic region of the cell and when activated, AR is imported into the nucleus. Initial hormonal therapy for prostate cancer involves lowering serum levels of testosterone to shut down AR activity. Despite initial patient responses to testosterone-depleting therapies, prostate cancer becomes refractory to hormonal therapy. Notably, AR is reactivated in hormone-refractory prostate cancer and reinstates its proliferative and survival activity.

Available for licensing is a novel chemical compound which is bifunctional and binds to AR. This compound is comprised of tubulin-binding and steroid receptor-binding moieties. This compound is designed to antagonize AR function in a nonclassical manner by several mechanisms and kills hormone-refractory prostate cells better than both functional moieties. This compound is a first-in-class of bifunctional steroid receptor binding agents that can antagonize steroid receptors in a variety of hormone-dependent diseases, such as breast and prostate cancer. CRADA Opportunity: The Medical Oncology Branch, National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize treatments of resistant prostate cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Improved Bacterial Host for Production of Anthrax Toxin Proteins and Vaccines: Bacillus anthracis BH450

Tue, 02 Sep 2008 01:00:00 GMT

Anthrax toxin has previously been made from various avirulent strains of Bacillus anthracis. The inventors have genetically engineered a new strain of B. anthracis with improved properties. The strain, designated BH450, is totally deficient in the ability to make spores and to produce a major extracellular protease designated Peptidase M4. The genetic lesions introduced are defined, true deletions, so there is no possibility of reversion. Inability to make spores assures that laboratories growing the strain will not become contaminated with the very stable anthrax spores. Inability to make peptidase M4 increases the stability of proteins such as anthrax toxin that are secreted to the culture medium. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Bacterial Diseases, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Bacillus anthracis BH450 strain. Please contact Dr. Andrei P. Pomerantsev at phone 301-451-9817 and/or email apomerantsev@niaid.nih.gov for more information.

Monoclonal Antibodies that Neutralize B. anthracis Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF)

Mon, 01 Sep 2008 05:00:00 GMT

Anthrax, whether resulting from natural or bioterrorist-associated exposure, is a constant threat to human health. The lethality of anthrax is primarily the result of the effects of anthrax toxin, which has 3 components: a receptor-binding protein known as "protective antigen" (PA) and 2 catalytic proteins known as "lethal factor" (LF) and "edema factor" (EF). Although production of an efficient anthrax vaccine is an ultimate goal, the benefits of vaccination can be expected only if a large proportion of the population at risk is immunized. The low incidence of anthrax suggests that large-scale vaccination may not be the most efficient means of controlling this disease. In contrast, passive administration of neutralizing human or chimpanzee monoclonal antibody to a subject at risk for anthrax or exposed to anthrax could provide immediate efficacy for emergency prophylaxis against or treatment of anthrax.

Four monoclonal antibodies (mAbs) against PA, three mAbs against LF and four mAbs specific for EF of anthrax were isolated from a phage display library generated from immunized chimpanzees. Two mAbs recognizing PA (W1 and W2), two anti-LF mAbs efficiently neutralized the cytotoxicity of lethal toxin in a macrophage lysis assay. One anti-EF mAb efficiently neutralized edema toxin in cell culture. All five neutralizing mAbs protected animals from anthrax toxin challenge. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Chimpanzee/human neutralizing monoclonal antibodies against anthrax toxins. Please contact Dr. Robert Purcell at 301-496-5090 for more information.

In Vitro Model for Hepatitis C Virion Production

Mon, 01 Sep 2008 09:00:00 GMT

This invention provides an in vitro hepatitis C virus (HCV) replication system that is capable of producing viral particles in a culture medium. Hepatitis C is a major public health problem, the development of therapeutics for which has been hampered by a lack of a robust model system to study the complete viral life cycle. This invention provides a new model system for the complete replication cycle of hepatitis C virus and virion production, assembly and release. The model is useful for screening antiviral agents against HCV.

A full length HCV construct, CG1b of genotype 1b which is known to be infectious, was placed between two ribozymes designed to generate the exact 5' and 3' ends of HCV when cleaved. Using this system, HCV proteins and positive and negative RNA strands have been shown to reproduce intracellularly, and viral particles that resemble authentic HCV virions are produced and secreted into the culture medium.

The patent application includes claims directed toward the following:

a construct comprising specific nucleic acid sequences including HCV genotype 1b, genotype 1a, genotype 2a or potentially other genotypes
a method for identifying a cell line that is permissive for infection with HCV
a method for propagating HCV in vitro
a method for screening agents capable of modulating HCV replication or activity
a method for testing the level of HCV replication or activity
a HCV vaccine comprising HCV virus particles

CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Liver Diseases Branch, is seeking parties interested in collaborative research directed toward molecular strategies for vaccine and antiviral development, and animal models of viral hepatitis C. Please contact Dr. T. Jake Liang at 301-496-1721, jliang@nih.gov or Cindy K. Fuchs, J.D. at cfuchs@mail.nih.gov for more information.

Compositions and Methods for Increasing Recombinant Protein Yields through the Modification of Cellular Properties

Mon, 01 Sep 2008 13:00:00 GMT

This technology relates to compositions and methods for improving the growth characteristics of cells engineered to produce biologically active products such as antibodies or glycosylated proteins. Featured is a method that uses gene candidates (e.g., cdkl3, siat7e, or lama4), or their expressed or inhibited products in cell lines, such as Human Embryonic Kidney (including HEK-293), HeLa, or Chinese Hamster Ovary (CHO). The gene expression modulates growth characteristics, such as adhesion properties, of the cell lines thereby increasing recombinant protein yields and reducing product production costs. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Biotechnology Core Laboratory, is seeking parties interested in collaborative research projects directed toward the use of this technology with cells for drug and vaccine production and development, including growth optimization, production and product recovery processes. For more information, please contact Dr. Joseph Shiloach, josephs@intra.niddk.nih.gov, or Rochelle S. Blaustein at Rochelle.Blaustein@nih.gov.

Methods for Preparing Bacillus anthracis Protective Antigen for Use in Vaccines

Mon, 01 Sep 2008 17:00:00 GMT

This invention relates to improved methods of preparing Bacillus anthracis protective antigen (PA) from a cell or organism, particularly a recombinant cell or microorganism, for use in vaccines. Production and purification methods of modified PA from a non-sporogenic strain of Bacillus anthracis are described. Specifically, a scalable fermentation and purification process is claimed that is suitable for vaccine development, and that produces almost three times more product than earlier-reported processes. This is accomplished using a biologically inactive protease-resistant PA variant in a protease-deficient non-sporogenic avirulent strain of B. anthracis (BH445). One of the PA variants described in the patent application lacks the furin and chymotrypsin cleavage sites. CRADA Opportunity: The National Institutes of Health is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of preparing Bacillus anthracis protective antigen (PA) from a cell or organism, particularly a recombinant cell or microorganism, for use in vaccines. Please contact Rochelle S. Blaustein, J.D., at 301/451-3636 or Rochelle.Blaustein@nih.gov for additional information.

Cross-Reactive Neutralizing Human Domain Antibody Against HIV-1

Fri, 01 Aug 2008 21:00:00 GMT

The invention describes the first identified anti-HIV human domain antibody (m36), which can potentially be used alone or synergistically with other anti-HIV antibodies and antiretroviral drugs as a therapeutic and/or preventative for HIV infection. It targets an epitope whose exposure is enhanced by binding of the HIV receptor CD4 to the HIV envelope glycoprotein (Env). M36 was identified by sequential panning of a newly developed large human VH library against Envs from different HIV-1 isolates. The antibody can neutralize HIV-1 primary isolates from different clades at low (nM) concentrations and due to its small size (14 kDa) is potentially able to efficiently penetrate lymphoid tissues where the virus replicates. The antibody is fairly well characterized and the inventors are generating derivatives of this antibody to improve the half-life and increase its potency and cross-reactivity. CRADA Opportunity: The National Cancer Institute CCR Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize domain antibodies and nanoantibodies against HIV. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

HIV Immunogen and Method of Making and Using Same

Sat, 02 Aug 2008 01:00:00 GMT

The invention describes composition and methods of preventing HIV infection using a truncated version of the HIV gp41 subunit of Env fused to human Fc through a flexible linker as a vaccine immunogen. This immunogen binds several broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies recently identified and developed by the inventor’s laboratory, including m44. m44 does not react with self-antigen suggesting that this immunogen may elicit antibodies which are not regulated by tolerance mechanisms, a problem suggested as the cause of failure for some of the gp41-based immunogens previously tested. Rabbits immunized with this fusion construct developed broad-neutralizing antibodies against several HIV-isolates from different clades in a cell line/pseudovirus assay with high titer. Preclinical testing of these novel immunogens in primate models is currently being planned. CRADA Opportunity: The NCI CCR Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods of Preventing Tissue Ischemia

Fri, 01 Aug 2008 05:00:00 GMT

Nitric oxide (NO) plays an important role as a major intrinsic vasodilator, and increases blood flow to tissues and organs. Disruption of this process leads to peripheral vascular disease, ischemic heart disease, stroke, diabetes, and many more significant diseases.

Researchers at the NIH have discovered that the matrix protein thrombospondin-1 blocks the beneficial effects of NO, and prevents it from dilating blood vessels and increasing blood flow to organs and tissues. Additionally, the inventors discovered that this regulation requires interaction with thrombospondin-1's cell receptor CD47. Murine studies revealed that, in the presence of NO, genetically altered mice, lacking either thrombospondin-1 or CD47, showed dramatically improved blood flow and tissue oxygenation. The inventors have also shown in both mice and pigs that by targeting thrombospondin-1 and/or CD47, blood flow can be dramatically increased to ischemic tissues. The same therapeutics also were found to protect tissues from ischemia/reperfusion injury.

Available for licensing and commercial development are:

Compositions and methods of treating tissue ischemia and/or tissue damage due to ischemia, increasing blood vessel diameter, blood flow and tissue perfusion in the presence of vascular disease including peripheral vascular disease, atherosclerotic vascular disease and stroke.
Compositions and methods for decreasing blood flow as in the case of cancer through mimicking the effects of thrombospondin-1 and CD47 on blood vessel diameter and blood flow.

CRADA Opportunity: The National Cancer Institute Center for Cancer Research, Laboratory of Pathology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutics targeting CD47 or thrombospondin-1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Large Semi-Synthetic Human Antibody Domain Fragment Library

Fri, 01 Aug 2008 09:00:00 GMT

Human monoclonal antibodies are important for the development of inhibitors, vaccines, diagnostic and research tools. Previously a large non-immune human antibody library (15 billion (15 x 10⁹) clones) was constructed from the lymph nodes, spleen and peripheral blood lymphocytes of 50 donors. One antibody, isolated from this library, includes a stop codon in the light chain but was still expressed and included a functional heavy chain. The VH domain exhibits high levels of expression and high solubility even in the absence of a light chain variable domain. This VH domain was used as a framework to construct a large human VH domain library (25 billion clones) by grafting naturally occurring complementarity determining regions (CDRs) from other human antibody libraries and randomly mutating one of the CDRs. This library has been used internally for selecting anti-HIV antibodies, viruses of biodefense interest and cancer-related antigens and is available for licensing as a biological material. Several high-affinity binders have already been identified.

The antibodies generated from this library are small (e.g., about more than 14 kDa), highly stable and can be expressed at high levels as monomers. The library permits the isolation of antibodies with favorable properties: affinity, stability, solubility, high levels of expression (at low cost), low rejection rates and low toxicity. CRADA Opportunity: The National Cancer Institute's Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Large Semi-Synthetic Human Antibody Domain Library. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Immunotoxins Made with Modified Cholix Toxin and Uses Thereof

Fri, 01 Aug 2008 13:00:00 GMT

Immunotoxins are chimeric molecules comprising an antibody targeting moiety and a toxin domain capable of killing a cell. Immunotoxins represent an important therapeutic tool for the treatment of cancer because they are able to specifically target cancer cells while ignoring healthy cells. The major drawback to immunotoxins is the development of neutralizing antibodies against the toxin portion of the immunotoxin. Many patients treated with Pseudomonas exotoxin A (PE) based immunotoxins develop neutralizing antibodies after the first administration. As a result, only one effective administration of a PE-based immunotoxin is often possible.

NIH inventors have created a novel immunotoxin, where the toxin portion is a truncated Cholera exotoxin (cholix toxin). Although cholix toxin retains strong functional and structural similarity to PE, neutralizing antibodies to PE do not affect the truncated cholix toxin. As a result, cholix toxin-based immunotoxins are of potential utility after a patient has developed neutralizing antibodies to PE. The ability to deliver two rounds of immunotoxins to a patient will increase the successful treatment of various diseases, including cancer. CRADA Opportunity: The National Cancer Institute, CCR, Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize immunotoxins composed of cholera exotoxin. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Identification and Characterization of Folliculin-Interacting Protein 2, FNIP2

Fri, 01 Aug 2008 17:00:00 GMT

The invention describes the identification and characterization of a FNIP1 homolog, folliculin-interacting protein 2 (FNIP2), that interacts with folliculin, the protein encoded by the FLCN gene, which is responsible for the Birt-Hogg-Dube' (BHD) syndrome. BHD is a dermatologic disorder associated with an increased risk for developing renal cancer, spontaneous pneumothorax and lung cysts. FNIP2 binds to the C-terminus of folliculin and to AMPK. Importantly, FNIP2 expression was elevated in renal tumors seen in BDH patients. This finding suggests that FNIP2 may serve as a biomarker for BHD. CRADA Opportunity: The Urologic Oncology Branch at the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize detection methods specific for FNIP2 to be used to screen FNIP2 as a biomarker for renal cancer. This may include development of an efficient FNIP2 antibody which does not cross react with FNIP1 for immunhistochemical screening of renal tumors for FNIP2 expression. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Enhanced T-cell Activation by Costimulation: A Potentially Novel Approach for the Prevention and/or Therapy of Cancer (Excluding Prostate Diseases and Melanoma) and for Infectious Diseases

Fri, 01 Aug 2008 21:00:00 GMT

Cancer immunotherapy is a recent approach where tumor associated antigens (TAAs), which are primarily expressed in human tumor cells and not expressed or minimally expressed in normal tissues, are employed to generate a tumor specific immune response. Specifically, these antigens serve as targets for the host immune system and elicit responses that results in tumor destruction. The initiation of an effective T-cell immune response to antigens requires two signals. The first one is antigen specific via the peptide/major histocompatibility complex and the second or "costimulatory" signal is required for cytokine production, proliferation, and other aspects of T-cell activation.

The present technology describes recombinant poxvirus vectors encoding at least three or more costimulatory molecules and tumor associated antigens (TAAs). The use of three costimulatory molecules such as B7.1, ICAM-1 and LFA-3 (TRICOM®) has been shown to act in synergy with several tumor antigens and antigen epitopes to activate T cells. The effects with TRICOM® were significantly greater than with one or two costimulatory molecules. Laboratory results support the greater effect of TRICOM® to activate both CD4+ and CD8+ T cells. The invention also describes the use of at least one target antigen or immunological epitope as an immunogen or vaccine in conjunction with TRICOM®. The antigens include but are not limited to carcinoembryonic antigen (CEA) and MUC-1. The combination of CEA, MUC-1, and TRICOM® is referred to as PANVAC®. CRADA Opportunity: A Cooperative Research and Development Agreement (CRADA) partner for the further co-development of this technology is currently being sought by the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI.

The CRADA partner will:

generate and characterize recombinant poxviruses expressing specific tumor-associated antigens, cytokines, and/or T-cell costimulatory factors,
analyze the recombinant poxviruses containing these genes with respect to appropriate expression of the encoded gene product(s),
supply adequate amounts of recombinant virus stocks for preclinical testing,
manufacture and test selected recombinant viruses for use in human clinical trials (with the exception of trials for prostatic diseases and melanoma),
submit Drug Master Files detailing the development, manufacture, and testing of live recombinant vaccines to support the NCI-sponsored IND and/or company-sponsored IND,
supply adequate amounts of clinical grade recombinant poxvirus vaccines for clinical trials conducted at the NCI Center for Cancer Research (CCR), and
provide adequate amounts of vaccines for extramural clinical trials, if agreed upon by the parties, and conduct clinical trials under company-sponsored or NCI-sponsored INDs.

NCI will:

provide genes of tumor-associated antigens, cytokines and other immunostimulatory molecules for incorporation into poxvirus vectors,
evaluate recombinant vectors in preclinical models alone and in combination therapies, and
conduct clinical trials (with the exception of trials for prostatic diseases and melanoma) of recombinant vaccines alone and in combination therapies.

If interested in a CRADA Opportunity, please submit a statement of interest and capability to Kevin Brand, J.D., in the NCI Technology Transfer Center, 6120 Executive Boulevard, Suite 450, Rockville MD 20852; telephone: 301/451-4566; email: kb229t@nih.gov.

Polyamine Compounds That Bind Tar RNA of HIV and Methods of Treating Viral Disorders

Sat, 02 Aug 2008 01:00:00 GMT

Current HIV treatment involves applying cocktail of drugs targeting either virus entry or one of three viral enzymes. Because patients eventually develop resistance to the cocktail, a new class of drugs is urgently needed. Current invention describes a new class of polyamine compounds that specifically bind to HIV RNA at micromolar range to prevent binding of viral RNA to viral proteins and therefore blocking viral replication. This differs with the mechanisms of current HIV drugs in the market and therefore offers new strategy in HIV treatment and prevention. Furthermore, this class of compound may aid future development of drugs targeting RNA. CRADA Opportunity: The NIDDK, Laboratory of Bioorganic Chemistry, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the application of TAR-binding polyamines for the treatment of HIV infections. Please contact Daniel Appella at 301-451-1052 or appellad@niddk.nih.gov for more information.

Broadly Neutralizing Anti-HIV Monoclonal Antibody That Targets a New Epitope on gp41

Fri, 01 Aug 2008 05:00:00 GMT

Blocking entry of HIV into cells and vaccine development against HIV are the prime targets of HIV therapy and prevention, respectively. Current invention describes a monoclonal Fab anti-HIV antibody isolated through panning against the chimeric construct NCCG-gp41 by Antibodies-by-Design (Morphosys). One of the antibodies has broadly neutralization ability against several HIV subtypes in an envelope-pseudotyped-virus neutralization assay. This antibody was also shown to have synergistic effect with a gp41-derived peptide discovered in this laboratory in inhibiting HIV-1 fusion. CRADA Opportunity: The NIH, Laboratory of Chemical Physics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this monoclonal Fab. Please contact Dr. G.M. Clore at 301-496-0782 and/or email at mariusc@mail.nih.gov for more information.

Fluorescent Cell Lines for Detection of DNA Damage

Fri, 01 Aug 2008 09:00:00 GMT

The Enhanced Level of Genomic instability 1 (ELG1) protein suppresses genomic instability caused by DNA damage. Cell lines for studying human ELG1 (hELG1) have been established that stably express a fusion protein combining hELG1 and either Green Fluorescent Protein (GFP) or Cyan Fluorescent Protein (CFP). It has been shown that the fluorescent hELG1 is an excellent reporter for DNA damage within the cell, with increased hELG1 localization to the cell nucleus upon exposure to a genotoxin. Therefore, these cell lines may have utility as a screening tool to detect genotoxic agents.

Available for licensing are the RPE cell line (immortalized normal retinal pigment epithelial cells) stably expressing hELG1-CFP, and the U2OS cell line (human osteosarcoma cells) stably expressing hELG1-GFP. CRADA Opportunity: The National Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the assay for detection of genotoxic agents using RPE cell line having hELG1-CFP. Please contact Menghang Xia or James Inglese at mxia@mail.nih.gov or jinglese@mail.nih.gov for more information.

Species-Independent A₃ Adenosine Receptor Agonists Which May Be Useful for Treating Ischemia, Controlling Inflammation, and Regulating Cell Proliferation

Fri, 01 Aug 2008 13:00:00 GMT

This invention claims species-independent agonists of A₃AR, specifically (N)-methanocarba adenine nucleosides and pharmaceutical compositions comprising such nucleosides. The A₃ adenosine receptor (A₃AR) subtype has been linked with helping protect the heart from ischemia, controlling inflammation, and regulating cell proliferation. Agonists of the human A₃AR subtype have been developed that are also selective for the mouse A₃AR while retaining selectivity for the human receptor. This solves a problem for clinical development because animal model testing is important for pre-clinical validation of drug function. Novel agonists have been made that exhibit as much as 6000x selectivity for A₃ versus A₁ in humans while retaining at least 400x selectivity for A₃ versus A₁ in mice. In addition, the molecules of the invention exhibit very low nanomolar affinity. This innovation will not only facilitate moving A₃ agonists into the clinical phase of drug development by being more amenable to animal studies, but also provide much greater selectivity in humans, and thereby potentially fewer side effects than drugs currently undergoing clinical trials. CRADA Opportunity: The NIDDK Laboratory of Bioorganic Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize A₃ Adenosine Receptor Agonists. Please contact Marguerite J. Miller at 301-496-9003 or millermarg@niddk.nih.gov for more information.

Extracellular Matrix Gene Chips to Detect Metastatic Tumors

Fri, 01 Aug 2008 17:00:00 GMT

Cancer mortality is primarily associated with metastatic disease and not the primary tumor. Recent evidence suggests that metastatic disease can be an early event and in the majority of patients metastasis starts by the time the disease is diagnosed. Currently however, approximately one third of patients without evidence of tumor dissemination at the time of surgical resection of the primary tumor subsequently develop distant metastases after the tumor is removed. Therefore there is a need for methods of characterizing the early metastatic process for better treatment of cancer.

This invention provides arrays which can be used for detecting the metastatic capacity of a tumor. In particular, these gene chips or microarrays detect the over-expression of the cancer-related extracellular matrix (ECM) modifier proteins Anakin and Bromodomain 4 (Brd4). It has been shown that ECM gene dysregulation is predictive of metastasis in breast cancer and recently Brd4 and Anakin have been identified as metastasis modifiers.

Using the signature profiles of Anakin and Brd4, the inventors have demonstrated that these genes predict survival outcome in affymetrix and glass slide based microarray experiments. As a result, screening for BRD4 and/or Anakin status in tumors could be an important prognostic test and may enable physicians to better stratify patients based on risk of recurrence and progression to metastatic disease. CRADA Opportunity: The National Cancer Institute Metastasis Susceptibility Section of the Laboratory of Cancer Biology and Genetics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize BRD4 and/or RRP1B (Anakin) prognostic tests. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Treatment of Alcoholism by Inhibition of the Neuropeptide Y Receptor

Fri, 01 Aug 2008 21:00:00 GMT

Aversive or anticraving medications are currently used to supplement behavioral treatment of alcohol dependence. However, there is a need for developing more effective medications than those available. Neuropeptide Y (NPY) is a neurotransmitter known for increasing appetite and possibly having a role in alcohol preference and dependence. This is likely to be mediated by activation of the post-synaptic NPY-Y1 receptor, but developing molecules suitable for human therapeutics that activate that receptor represents a major challenge. Researchers at the NIH have now shown that administering antagonists of the presynaptic Y2 receptor of NPY decreases alcohol consumption and may be a valuable new treatment for alcoholism. CRADA Opportunity: The National Institute on Alcohol Abuse and Alcoholism, Laboratory of Clinical and Translational Studies is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antagonism of presynaptic NPY Y2 receptors for treatment of alcohol dependence. Please contact Peter B. Silverman at psilverm@mail.nih.gov for more information.

Methods for Promoting Stem Cell Proliferation and Survival

Sat, 02 Aug 2008 01:00:00 GMT

Regenerative medicine has the potential to treat numerous human diseases and afflictions including neurodegenerative disorders and spinal cord injury that are typically insidious and worsen over time. This technology consists of a promising treatment method that coaxes stem cells into a state that promotes survival and proliferation. Two critical elements of this approach involve identifying the target niche and determining the pharmacological agents that can be used to promote stem cell regeneration.

Specifically, this technology consists of a method to activate the endogenous neural stem cells (NSCs) to promote their survival and yield using angiopoietin-2 and a cocktail of ligands and growth factors. This method has demonstrated that it can significantly improve the yield of stem cell cultures in vitro and stimulate behavioral recovery in a model of Parkinson's disease in vivo. This method is applicable to a variety of stem cell types including embryonic stem cells, adult spinal cord cells, and pericyctes from blood vessels. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents with activity on proliferation and/or differentiation of stem cells. Please contact Laurie Arrants at 301-435-3112 or ArrantsL@ninds.nih.gov or Martha Lubet at 301-435-3120 or lubetm@mail.nih.gov for more information.

Transgenic Mouse Model Useful for the Study of Myelodysplastic Syndrome

Fri, 01 Aug 2008 05:00:00 GMT

Myelodysplastic syndrome (MDS) is collection of closely related blood diseases that arise in the bone marrow characterized by anemia, neutropenia, and thrombocytopenia resulting from hematopoietic stem cell disorders. A variety of genetic aberrations have been associated with MDS, including chromosomal translocations of the NUP98 gene. The only current curative therapy for MDS is allogeneic bone marrow transplant. Without bone marrow transplant, patients either die of progressive pancytopenia or following transformation of MDS to acute myeloid leukemia. Progress in understanding and treating MDS has been hampered by a lack of an animal model that accurately recapitulates all of the features of human MDS. Utilizing a NUP98-HOXD13 (hereafter NHD13) fusion gene, a mouse model was developed to elucidate the biology of MDS. Genetically engineered mice that express an NHD13 transgene display all of the phenotypic features of MDS including peripheral blood cytopenia, bone marrow dysplasia, and transformation to acute leukemia. These mice provide an accurate preclinical model for MDS. CRADA Opportunity: The Leukemia Biology Section, Genetics Branch, National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the NHD13 mouse model. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

New Tumor Endothelial Markers: Genes that Distinguish Physiological and Pathological Angiogenesis

Fri, 01 Aug 2008 09:00:00 GMT

Angiogenesis, the formation of new blood vessels, is associated with normal physiological processes such as wound healing, ovulation or menstruation as well as with many diseases. Presently, it is thought to be required for the progressive growth of solid tumors and age-related macular degeneration. Lack of disease-specific endothelial markers has hindered the development of cancer therapies targeted against angiogenesis.

This invention describes specific markers that can be used to identify tumor angiogenesis, separate from normal physiological angiogenesis. Several markers have been identified which may serve as potential targets for tumor vessels by using comparative gene expression analysis on various normal and tumor endothelial cells. Furthermore, the invention describes several organ-specific endothelial markers that can aid in the selective delivery of molecular medicine to specific sites. For example, brain endothelial markers (BEMs) and liver endothelial markers (LEMs) described herein could potentially be used to direct molecular medicine specifically to these tissues.

The novel tumor endothelial markers (TEMs) described in this invention also have potential diagnostic ability. These markers can be used to distinguish between normal and tumor tissues. Some of the secreted TEMs can serve as surrogate markers in the determination of the optimum biological dose (OBD) for the current anti-angiogenic drugs in clinical trials. CRADA Opportunity: The NIH National Cancer Institute, Tumor Angiogenesis Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize specific biomarkers that can be used to identify tumor angiogenesis. Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.

Methods of Treating and Preventing Renal Cancer using a Dimethane Sulfonate Compound

Fri, 01 Aug 2008 13:00:00 GMT

Currently only a few small molecule inhibitors are effective in patients with renal cell carcinoma. Approximately 30,000 patients per year are diagnosed with this disease but many of them are untreatable because of intrinsic drug resistance, and efficient drug transport and detoxification mechanisms. This invention described and claimed in the patent application describes a series of dimethane sulfonate compounds based on NSC 281612 that are suitable for the treatment of renal cancer. Compositions comprising a pharmaceutically-acceptable carrier and a compound, or a salt suitable for use in the treatment or prevention of renal cancer are also described. The anti-tumor activity of NSC 281612 has been established in vivo against human renal tumor xenografts in mice. Suitable dosing and administration schedules for treatment of renal tumors have also been determined in this study. CRADA Opportunity: The National Cancer Institute, Screening Technologies Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize biomarker assays for clinical utility (potential molecular targets have been identified). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Compounds and Methods to Use Them to Treat Gastric, Colon, Lung, Breast, Ovarian and Pancreatic Tumors

Fri, 01 Aug 2008 17:00:00 GMT

Systemic toxicity of drugs is one of the most serious problems in cancer chemotherapy and frequently is dose limiting. Specific delivery of cytotoxic drugs to cancer cells remains among the most intractable problems of cancer therapy. Targeted delivery of anti-proliferation drugs through the cell surface receptors that are over expressed on cancer cells can reduce systemic toxicity and increase effectiveness of a treatment.

The present invention describes cytotoxic compounds with an intracellular target that can selectively enter tumor cells through specific receptors on the cell surface. The invention also describes a conjugate comprising a cytotoxic agent, a linker arm and a ligand capable of delivering a cytotoxic agent in a cell specific manner. Such conjugates of a cytotoxic agent and a ligand (delivery moiety) have increased selectivity for tumor cells. The toxic moiety and the ligand are joined by a linker arm that is stable in circulation, but is easily cleaved in lysosomes upon internalization of the conjugate. A panel of compounds comprised of a variety of cytotoxic warheads, against various intracellular targets linked to an assortment of ligands, has been developed and tested in a model system. Ligand moieties of these conjugates are capable of specific delivery of cytotoxic agents to receptors that are frequently over expressed in gastric, colon, lung, breast, ovarian and pancreatic tumors. These compounds have the potential to be highly effective anti-tumor agents with considerably little negative effect. This disclosed technology could provide new and exciting methodologies to treat cancer. CRADA Opportunity: The National Cancer Institute Structural Biophysics Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Compounds and Methods to Use Them to Treat Gastric, Colon, Lung, Breast, Ovarian and Pancreatic Tumors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

T-Cell Enumeration Using Dried Blood Spots as a Surrogate for CD4+ T-Cell Counts to Monitor HIV+ Patients

Tue, 01 Jul 2008 21:00:00 GMT

Available for licensing and commercial development is a novel method for enumerating T-cells in HIV+ patients using dried blood spots, avoiding the need for fresh blood samples. The method relies on the distinctive nature of the TCR-beta gene, which undergoes a rearrangement during T-cell development that is required to produce a functional T-cell receptor protein. Since only mature T-cells contain a rearranged TCR-beta gene, the method quantifies the number of T-cells in a patient sample by quantifying the number of cells that contain a rearranged TCR-beta gene. In addition to dried blood spots, the assay can be also used with a wide variety of sample types from which T-cell counts were previously impossible to obtain, such as swabs and tissue slides. In addition, this method can be used for monitoring of a variety of T-cell leukemias/lymphomas, and easily adapted to monitor B-cell levels found in B-cell leukemias/lymphomas.

The assay was found to accurately predict TCR-beta levels (r=0.985, p<0.0001), and to correlate well with known CD4 counts (r=0.670, p<0.0001). Therefore, this novel method can be used to monitor HIV infection in order to determine antiretroviral therapy (ART) initiation and monitoring. A large international effort has been made to provide ART to the more then 33 million HIV+ people worldwide, but significant hurdles remain to large-scale implementation due to the lack of medical and laboratory infrastructure found in the developing world, where the majority of HIV+ individuals are found. In particular, a CD4 count, which requires fresh whole blood, a reliable cold-transport chain, and an expensive FACS based reader, is required to monitor patients and determine ART initiation. This requirement has become one of the largest impediments to expanding ART around the world. Therefore, this novel method provides a superior functional assay for HIV disease staging that does not require cold storage or fresh sample processing. Dried blood spots are an ideal sample collection method for large scale monitoring in the developing world due to the relatively simple manner in which samples can be obtained and the high stability of the sample in the absence of refrigeration. This method provides an easier and less expensive method for HIV monitoring for the developing world, and could be also used as an at home monitoring system for HIV-infected patients in developed countries. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, International HIV and STD Unit, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize TCR-beta enumeration to monitor HIV+ patients, as well as other diseases or syndromes in which T-cell monitoring is commonly performed. Please contact Andrew Redd, PhD at 410-614-0813 or aredd2@jhmi.edu for more information.

Prolactin Receptor Antibodies as a Diagnostic Marker and Therapeutic Agent for Cancer

Wed, 02 Jul 2008 01:00:00 GMT

Prolactin is a key hormone in the normal breast development and plays a role in the growth and development of other major organs such as the prostate. The biologic function of prolactin is mediated by specific receptors on the cell surface, with breast cancer cells containing more receptors than normal tissue. The prolactin receptor, a member of the large class-1 cytokine receptor superfamily, has three major isoforms that are cell associated. The specific isoform concentration and distribution determines biological activity and may determine susceptibility to antiprolactin drugs.

This technology describes several antibodies, both polyclonal and monoclonal, to the prolactin receptor. These include antibodies to the three major isoforms: the long isoform (LF), two short isoforms (SF1a and SF1b), and the secreted form, prolactin receptor delta7-11. These antibodies can be used for the diagnosis of prolactin sensitive tumors. Furthermore, the presence of the secreted prolactin receptor delta7-11 may provide a blood test for prolactin responsive tumors. CRADA Opportunity: The National Cancer Institute, Mammary Biology and Tumorigenesis Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize isoform specific antibodies to the human prolactin receptor. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Rapid and Sensitive Detection of Nucleic Acid Sequence Variations

Tue, 01 Jul 2008 05:00:00 GMT

The ability to easily detect small mutations in nucleic acids, such as single base substitutions, can provide a powerful tool for use in cancer detection, perinatal screens for inherited diseases, and analysis of genetic polymorphisms such as genetic mapping or for identification purposes. Current approaches make use of the mismatch that occurs between complimentary strands of DNA when there is a genetic mutation, the electrophoretic mobility differences caused by small sequence changes, and chemicals or enzymes that can cleave heteroduplex sites. Some of these methods, however, prove to be too cumbersome, are unable to pinpoint mutations, only detect a subset of mutations, or involve the use of hazardous materials.

The current invention takes advantage of the ability of transposons, or mobile genetic elements, to move from one part of the genome to another by the cleavage and joining of their sequences into the target site; a reaction facilitated by a transposase enzyme. The phage Mu transposase is capable of inserting the right end sequence of the Mu transposon into any DNA sequence both in vitro and in vivo. The surprising discovery that the Mu transposase displays a strong preference for inserting Mu-end DNA into mismatched sites, the very sites which occur when DNA is mutated and paired with its complimentary strand that does not have the corresponding mutation, makes it a powerful tool for detecting variations in nucleic acid sequences. In this system, the transposition of Mu-end DNA at a site is used to indicate the presence of a nucleic acid mismatch or mutation at that site. The invention can be used with labeled Mu-end DNA to further facilitate the precise mapping of the mutations. This specificity allows Mu to detect even single base mutations amongst a large quantity of non-specific DNA. The Mu detection system is simple, rapid, and highly sensitive compared to current methods and can find a broad range of use in genetic research and the diagnosis of several diseases such as cystic fibrosis, spinal and bulbar muscular dystrophy, human fragile-X syndrome and Huntington’s disease. CRADA Opportunity: The Section on Genetic Mechanisms, LMB, NIDDK is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Mu transposition system as a tool for mutation detection and other genetic research/manipulation. Please contact Kiyoshi Mizuuchi at kmizu@helix.nih.gov for more information.

Treatment of Skin Conditions Using DKK1

Tue, 01 Jul 2008 09:00:00 GMT

This invention discloses a method for inducing non-palmoplantar skin (skin of the trunk, arms, and face etc.) to develop characteristics of palmoplantar skin (skin of the soles and palms). This effect is achieved by use of Dickkopf 1 (DKK1), a protein which is highly expressed by palmoplantar fibroblasts and is a known antagonist of the Wnt signaling pathway. Topical application of DKK1 to non-palmoplantar skin induces the development of increased skin thickness, decreased pigmentation, and decreased hair growth. These characteristics are desirable for treating several dermatological conditions.

The skin thickening caused by topical application of DKK1 can be useful for skin grafts, and skin ulcers or abrasions. Decreased skin pigmentation, experimentally achieved by either topical or in vitro application of DKK1, may be desirable for conditions such as uneven skin pigmentation, pigmented birthmarks, or post inflammatory pigmentation. Suppressed hair growth may be cosmetically desirable for some areas of the skin, and in conditions such hypertrichosis, adrenal hyperplasia, or polycystic ovarian syndrome. DKK1 treatment may also be important for treating or preventing certain melanomas which involve hyperplastic or pre-malignant lesions. CRADA Opportunity: The National Cancer Institute Laboratory of Cell Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of DKK1 or a bioactive fragment of DKK1 to treat abnormal pigmentation of the skin or to regulate hair growth. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A New Pot1 Variant Gene as a Diagnostic Biomarker for Hereditary Non-polyposis Colorectal Cancer

Tue, 01 Jul 2008 13:00:00 GMT

The diagnosis of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is difficult because the disease lacks phenotypic signs that might facilitate its presymptomatic diagnosis. This invention is based on the identification of a new splice variant of a gene that appears to exist specifically in HNPCC, namely “Pot1” or “Protection of Telomeres.” Pot1 has a critical role in ensuring chromosome stability by binding to telomeres. The invention presents a variant of Pot1 that is present in mismatch repair-deficient, but not proficient, cancer cell lines and primary, non-tumor tissue samples. The presence of this variant may be useful both as a diagnostic marker for HNPCC, and as a new therapeutic target for the treatment of HNPCC. CRADA Opportunity: The National Cancer Institute Laboratory of Human Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize biomarkers of colon cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Cripto-1 as a Biomarker for Cardiac Ischemia

Tue, 01 Jul 2008 17:00:00 GMT

Ischemic heart disease is a major cause of human cardiac morbidity and mortality, affecting over 14 million people in the United States alone. Current detection of cardiac ischemia relies upon identification of electrocardiographic anomalies and the release of cardiac markers from the damaged myocardial tissue. Unfortunately, patients with acute myocardial infarction are often insensitive to these tests during the early phases of intervention and as a result more markers for cardiac ischemic disease are needed.

This technology describes Cripto-1 as a biomarker for infarcted cardiac tissues. Cripto-1 is a member of the epidermal growth factor (EGF)-related proteins and is currently thought to play an important role in several cancers. The present invention shows that Cripto-1 is overexpressed in infarcted myocardial tissue, and not expressed or weakly expressed in non-infarct related heart disease tissues and normal tissues. Furthermore, the overexpression of Cripto-1 correlates with the hypoxia-inducible factor-1-alpha indicating specificity to ischemic heart tissue. The expression of Cripto-1 has also been shown to be highly expressed in stem cells, which may have an important role in the repair of damaged myocardial tissue. Thus, this technology could represent a new biomarker for the diagnosis of myocardial infarction as well as a surrogate biomarker to monitor the healing process including regenerative stem cell activity of the infarcted myocardial tissue. CRADA Opportunity: The National Cancer Institute Mammary Biology and Tumorigenesis Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Cripto-1 as a biomarker for cardiac ischemia. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Cripto-1 Represents a Biomarker for Chronic Inflammatory Diseases

Tue, 01 Jul 2008 21:00:00 GMT

Chronic inflammatory bowel disease (IBD) (e.g. Crohn’s disease and ulcerative colitis) and chronic inflammatory arthropathy such as rheumatoid arthritis represent an enormous socio-economic burden due to the cost for long term medication and rehabilitation and the decreased productivity due to periods of acute recurrences. A major characteristic of these diseases is the tissue infiltration of specific CD4+ T cells that sustain inflammation by secreting cytokines. One of these cytokines, TNF-alpha, is a current therapeutic target for the treatment of these chronic inflammatory diseases.

This technology describes Cripto-1 as a biomarker for chronic inflammatory diseases. Cripto-1, an epidermal growth factor (EGF)-related protein, shows higher expression levels in tissue sections of Crohn’s disease, ulcerative colitis, and rheumatoid arthritis as compared to adjacent unaffected areas. Moreover, the inventors show that the response to Cripto-1 is not due to a generic immune response, and Cripto-1 expression increases the expression of TNF-alpha in CD4+ T cells in tissues affected by chronic inflammatory disease. As a result, this technology could be used as a diagnostic biomarker for chronic inflammatory diseases as well as a novel therapeutic target to help control TNF-alpha in chronic inflammatory diseases. CRADA Opportunity: The National Cancer Institute Mammary Biology and Tumorigenesis Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Cripto-1 as a biomarker for chronic inflammatory diseases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method for Detection and Quantification of PLK1 Expression and Activity

Wed, 02 Jul 2008 01:00:00 GMT

Polo-like kinase 1 (Plk1) plays a role in the regulation of the cell cycle and control of cellular proliferation. Because Plk1 is associated with neoplastic transformation of human cells, expression of this protein has been proposed as a prognostic marker for many types of malignancies. In mammalian cells, four Plks exist, but their expression patterns and functions appear to be distinct from each other. Available for licensing is a Plk1 ELISA assay using peptide substrates that are specific for Plk1, in that they are phosphorylated and bound by Plk1, but not by the related polo kinases Plk2, Plk3 and Plk4.

By exploiting a unique Plk1-dependent phosphorylation and binding property, an easy and reliable ELISA assay has been developed to quantify Plk1 expression levels and kinase activity. With this highly sensitive assay, Plk1 activity can be measured with 2-20 microgram of total lysates without immunoprecipitation or purification steps. Since deregulated Plk1 expression has been suggested as a prognostic marker for a wide range of human malignancies, this assay may provide an innovative tool for assessing the predisposition for cancer development, monitoring cancer progression, and estimating the prognosis of various types of cancer patients. CRADA Opportunity: The National Cancer Institute, Laboratory of Metabolism is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the PLK1 ELISA assay described above. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Single Nucleotide Polymorphism Detection by DNA Melting Analysis

Tue, 01 Jul 2008 05:00:00 GMT

A Single Nucleotide Polymorphism (SNP) is defined as a single base pair difference occurring between members of the same species, or between paired chromosomes in an individual. Some SNPs have been associated with disease traits, and may predispose an individual to a disease or may influence that individual's response to therapeutic agents. There are several high-throughput methods that can detect SNPs of moderate to high abundance, where the polymorphism frequency is greater than ten percent. However, SNPs that alter gene expression or affect the structure of a gene product are often of much lower abundance, with allele frequency of around one percent. Thus, there is a need to devise high-throughput, inexpensive and efficient methods for their detection.

The patent discloses methods for accurately detecting nucleotide sequence variations, such as polymorphisms, deletions, insertions or inversions, by comparison of DNA melting profiles. Methods of detecting single nucleotide sequence variations within arrays are also disclosed, as are methods of detecting mutations correlated with genetic disease. CRADA Opportunity: The National Institute on Alcohol Abuse and Alcoholism Section on Molecular Genetics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize single nucleotide polymorphism detection by melting analysis . Please contact Dr. Robert Lipsky at 301/402-5591 or rlipsky@mail.nih.gov for more information.

Use of Human Gamma Satellite Insulator Sequences to Prevent Gene Silencing and Allow for Long Term Expression of Integrated Transgenes

Tue, 01 Jul 2008 09:00:00 GMT

The lack of stable expression of transgenes in target cell lines remains a serious problem for gene therapy and cellular reprogramming approaches. Once integrated into chromosomes, the expression of these transgenes may be regulated by epigenetic effects of the surrounding chromatin. These position effects, which include transgene silencing and expression variegation, are often associated with changes in the chromatin structure, and are capable of inhibiting gene expression and neutralizing the intended effect of the inserted transgene.

Experimental results suggest that gene position effects can be partially overcome by flanking the transgene with regulatory elements called chromatin insulators which work by establishing defined domains of transcriptional activity within the eukaryotic genome. These insulators can partially overcome position effects by shielding the promoters from the influence of neighboring regulatory elements, or by preventing the spread of heterochromatin which can lead to subsequent gene silencing.

This invention discloses the use of gamma satellite DNA, residing in the pericentromeric region of human chromosomes, as highly efficient chromatin insulators. These insulators have a remarkable ability to overcome position effects and prevent the silencing of transgenes. When human chromosome 8 gamma satellite sequences were used as flanking DNA for eGFP (enhanced green fluorescent protein) gene expression in mouse erythroleukemia (MEL) cells, stable transgene expression was recorded for well over eight months. Until recently, no chromatin insulator sequences were known to completely prevent gene silencing on a long term basis in transfected cells. The human gamma-satellite sequences demonstrate a higher efficiency than any known chromatin insulator identified so far in intergenic regions, and may have invaluable applications in the fields of gene therapy, protein expression, and cellular reprogramming where adequate expression of the transgene is essential for long term therapeutic or developmental success. CRADA Opportunity: The National Cancer Institute Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize gamma-satellite DNA insulators for stable transgene expression in ectopic chromosomal sites and in Human Artificial Chromosomes (HACs). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel O-GLcNAcase Inhibitor and Fluorogenic Substrate as a Tool for Diagnosing Type 2 Diabetes

Tue, 01 Jul 2008 13:00:00 GMT

NIH researchers have synthesized a novel analogue of O-(2-acet-amido-2-deoxy-D-glycopyrano-sylidene)amino-N-phenylcarbamate (PUGNAc), which bears an extension on the N-acetyl moiety. This modified PUGNAc acts as a selective inhibitor of O-GlcNAcase; an enzyme that removes N-acetylglucosamine from nuclear and cytoplasmic proteins, and whose inhibition is associated with the development of Type 2 diabetes. The most desirable feature of this new compound is its ability to specifically inhibit O-GlcNAcase without targeting the related hexosaminidase A (HEX A) and hexoaminidase B (HEX B) enzymes. This unique property distinguishes it from the original PUGNAc and other compounds which inhibit O-GlcNAcase as well as other enzymes. It also has a smaller inhibitory effect on O-GlcNAcase compared to the original PUGNAc. These properties make the modified PUGNAc useful for diagnostic or therapeutic applications involving Type 2 diabetes.

A fluorescent derivative of the modified PUGNAc has also been developed. Modified PUGNAc, conjugated to a fluorescent moiety such as 4-methylumbelliferone, can serve as a substrate for O-GlcNAcase without inhibiting HEX A. This allows the fluorescently labeled compound to be used for measuring O-GlcNAcase enzyme activity, and thus provide a means of diagnosing Type 2 diabetes in human blood or tissue samples. Previous reagents have monitored other Type 2 diabetes related enzymes, but with much less specificity. Recent studies that link mutations of the MGEA5 gene (which codes for O-GlcNAcase) to Type 2 diabetes provide further support for the use of the fluorescent derivative as a potent tool for diagnosing the disease. The fluorogenic derivative may also be used as a novel imaging agent for assessing O-GlcNAcase function in-vivo. CRADA Opportunity: The NIDDK Laboratory of Cell Biochemistry and Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize modified PUGNAc for prevention or treatment of Type 2 diabetes. Please contact Cindy K. Fuchs, J.D. at 301-451-3636 or cfuchs@mail.nih.gov for more information.

A Novel Therapeutic Strategy for the Treatment of Hyperpigmentation and Melanoma

Tue, 01 Jul 2008 17:00:00 GMT

The present invention describes that the transcription factor SOX9 is expressed by normal human melanocytes in vitro and in the skin in vivo, and that over-expression of SOX9 decreases the proliferation of mouse and human melanoma cell lines via several pathways. Furthermore, SOX9 (or its bioactive derivatives) appears to be potentially useful in inducing skin pigmentation, may inhibit the proliferation of melanoma cells and increase their sensitivity to retinoic acid, which could be used to treat melanoma. CRADA Opportunity: The National Cancer Institute Laboratory of Cell Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the regulation of SOX9 function as a strategy to treat melanoma, modulate skin pigmentation and/or ameliorate skin pigmentary disorders. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view this NCI collaborative opportunity announcement. To view an NCI co-development collaborative opportunity announcement for SOX9 and/or NRG-1 function, click here.

A New Method for Screening of Anti-tumor Agents

Tue, 01 Jul 2008 21:00:00 GMT

Astrocytomas and glioblastoma multiforme are the most common forms of malignant brain cancer, and are often unresponsive to surgical removal and pharmacological therapy. The 5 year survival rate of glioblastoma is 5%, thus, making it necessary for the identification of more effective anti-tumor agents. Individuals with the familial cancer syndrome neurofibromatosis type 1 are predisposed to developing multiple tumors including astrocytoma and glioblastoma.

Scientists at NCI have discovered a new technology that will help screen multiple anti-tumor and anti-neurofibromatosis agents in a high throughput assay by using an astrocytoma cell line (KR158) that expresses the luciferase gene under the influence of dual promoters, E2F and CMV.

This new technology distinguishes between cytostatic and cytotoxic compounds, thereby significantly reducing the time and cost required to screen anti-tumor agents. CRADA Opportunity: The National Cancer Institute Mouse Cancer Genetics Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-astrocytoma or anti-neurofibromatosis therapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Therapeutic Application of Fatty Acid Amide Hydrolase Inhibitors

Wed, 02 Jul 2008 01:00:00 GMT

The enzyme fatty acid amide hydrolase (FAAH) is responsible for the degradation of the lipid anandamide. This is a cannabinoid naturally secreted from both the brain and body. Cannabinoid receptors mediate blood pressure, pain sensation, hunger and anxiety among other actions. Drugs inhibiting FAAH increase cannabinoid receptor activity in a manner distinct from cannabinoid agonists to treat hypertension, relieve pain or have other therapeutic effect with lessened side effects. CRADA Opportunity: The NIAAA Laboratory of Physiologic Studies is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize fatty acid amide hydrolase inhibitors. Please contact Peter B. Silverman (psilverm@mail.nih.gov) for more information.

A2 Adenosine Receptor Agonists

Tue, 01 Jul 2008 05:00:00 GMT

Four adenosine receptor subtypes exist, namely A₁, A_2A, A_2B and A₃, each with different functions, tissue distributions and ligand coupling abilities. While activation of A_2B AR can induce angiogenesis, reduce vascular permeabilization, increase production of the anti-inflammatory cytokine IL-10, increase chloride secretion in epithelial cells or increase release of inflammatory mediators from human and canine mast cells, there still remains a need for A_2B receptor agonists for clinical use.

Recognizing that an unmet medical need exists, the inventors synthesized an assortment of adenosine derivatives with the goal of preparing highly potent and selective A_2B receptor agonists. They identified a compound as a full agonist at the A_2A and A_2B adenosine receptors, capable of reducing infarct size in rabbit hearts induced by 30 minutes of ischemia. As activation of A_2A and A_2B receptors induces a cardioprotective effect and this compound activates both A_2A and A_2B receptors, this compound may be beneficial for protecting against myocardial ischemia/reperfusion injury.

Available for licensing and commercial development are compositions and methods of use of A2 adenosine receptor (AR) agonists for treating conditions modulated by A_2A and A_2B ARs including myocardial ischemia, reperfusion injury, cystic fibrosis, erectile dysfunction, inflammation, restenosis and septic shock. CRADA Opportunity: The NIDDK Laboratory of Bioorganic Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize A_2A and A_2B adenosine receptor agonists. Please contact Rochelle S. Blaustein at (301) 451-3636 or Rochelle.Blaustein@nih.gov for more information.

Tendon Stem Cells

Tue, 01 Jul 2008 09:00:00 GMT

Tendon injuries due to trauma and overuse are common clinical problems that result in significant pain and loss of mobility. Tendon injuries are slow to heal and the healed tendon rarely matches the original in mechanical strength and structural integrity. Due to a limited understanding of basic tendon biology, development of new treatment options for injured tendons has posed significant challenges.

This invention relates to a cell based therapy. Specifically, it relates to the isolation and enrichment of stem cells from adult tendons, known as tendon stem progenitor cells, that can form tendon structures and are capable of integrating into bones to form enthesis-like structures. Two extra-cellular matrix proteoglycans, biglycan and fibromodulin, further assist in the maintenance and multiplication of these tendon stem cells. CRADA Opportunity: The NIDCR, Molecular Biology of Bones and Teeth Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of tendon stem cells. Please contact Marian Young at 301-496-8860 or myoung@dir.nidcr.nih.gov.

TGF-beta Gene Expression Signature in Cancer Prognosis

Tue, 01 Jul 2008 13:00:00 GMT

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, and it is very heterogeneous in terms of its clinical presentation as well as genomic and transcriptomic patterns. This heterogeneity and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification.

Available for licensing is a novel temporal TGF-beta gene expression signature that predicts HCC patient clinical outcomes. Patients with tumors expressing late TGF-beta responsive genes had a malignant prognosis and an invasive tumor phenotype as evaluated by decreased survival time, increased tumor recurrence, and vascular invasion rate. Additionally, this signature may also be able to prognose other cancers, including lung cancer. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Experimental Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a novel temporal TGF-beta gene expression signature that predicts HCC patient clinical outcomes. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Steroid Derivatives as Inhibitors of Human Tyrosyl-DNA Phosphodiesterase (Tdp1)

Tue, 01 Jul 2008 17:00:00 GMT

Tyrosyl-DNA phosphodiesterase (Tdp1) is an enzyme that repairs topoisomerase I (Top1)-mediated DNA damage induced by chemotherapeutic agents and ubiquitous DNA lesions that interfere with transcription. The current technology are steroid derivatives that human inhibit Tdp1.

Currently, there are various types of Top1 inhibitors used in chemotherapy, e.g., camptothecin. However, Tdp1 inhibitors are expected to be effective in combination therapy with Top1 inhibitors for the treatment of cancers. Combining Tdp1 inhibitors with Top1 inhibitors would allow Tdp1 to potentiate the antiproliferative activity of Top1 inhibitors. In addition to Tdp1’s effect on Top1, Tdp1 inhibitors can also exhibit antitumor activity independently, as tumors are shown to have excess free radicals, and Tdp1 repairs DNA damage by oxygen radicals. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of Tyrosyl-DNA phosphodiesterase (Tdp1). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Flow-Through Thermal-Expansion-Compensated Microcells for Analytical Transmission Infrared Spectroscopy

Tue, 01 Jul 2008 21:00:00 GMT

Available for licensing and commercial distribution are optical cells spectroscopically stable and can be used for spectroscopic measurement in transmission, sample reflection, back plate reflection, emission, or scattering modes. The cell allows fluid in a sample space to be exchanged without separating a front or a back plate from a spacer, allows a solid sample to be placed in or removed from the sample space, requires only a small amount of sample, and allows for different sample gaps to be easily and inexpensively set. Alternatively, the spacers can be manufactured using a hydrocarbon-resistant polymer so that samples dissolved in organic solvents can be used without the risk of changing the spectral properties of the microcell and solvent leakage from the sample space. The inventive cell and methods allow spectral measurements to be taken over wavelengths ranging at least from the mid-infrared to the vacuum ultraviolet, provide a simple path for light traveling through a sample, and allow fast kinetic processes to be detected and monitored reproducibly and sensitively.

CRADA Opportunity: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Physical Biochemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize microcells for infrared and other spectroscopies and their applications to pathology diagnostics. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel Isoform of KCNH2 for the Treatment of Schizophrenia

Mon, 02 Jun 2008 01:00:00 GMT

Researchers at the NIH report the discovery and characterization of a novel isoform of the voltage-gated potassium channel KCNH2. This novel isoform is shown to control neurological firing and has implication as a genetic risk factor for schizophrenia. It is highly expressed in the hippocampus of schizophrenic patients and also in normal individuals who carry risk-associated alleles of KCNH2. This novel isoform may be a suitable target for drug development as is it minimally expressed in the heart with the potential to exert less adverse cardiovascular side-effects, which is often a consequence of currently available antipsychotic drugs.

Available for licensing and commercial development are nucleic acids, polypeptides and antibodies specific for this novel isoform, as well as methods of screening for therapeutic agents and predicting susceptibility to schizophrenia. CRADA Opportunity: The NIMH Clinical Brain Disorders Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize potassium channel isoform associated with schizophrenia. Please contact Suzanne Winfield at 301-402-4324 / winfiels@mail.nih.gov for more information.

Novel Fluorinated Dmt-Tic Analogues for Use as PET Radiotracers

Sun, 01 Jun 2008 05:00:00 GMT

Researchers at the NIH have developed fluorine-18 (¹⁸F) labeled analogues specific for the delta-opioid receptors. These radioligands include analogues of the Dmt-Tic pharmacophore, containing a delta-opioid receptor antagonist that may be useful for imaging opioid receptors expressed in lung malignant tumors or other peripheral tumors that express delta-opioid receptors. This methodology might be readily applicable to Dmt-Tic pharmacophoric ligands that exhibit dual antagonism for delta-/mu-opioid receptors.

Studies by the inventors have shown that injected radioligand failed to cross the blood-brain barrier (BBB) of rats; therefore, these compounds could serve as radiotracers for assessing and locating certain carcinomas that contain high levels of delta-opioid receptors, such as lung, breast and/or colon cancers. Since there is an increasing demand of radioligands for in vivo imaging of peripheral opioid receptors, this technology has the potential of enhancing current practices of PET imaging in oncology.

Available for licensing are compositions and methods of locating delta- and/or mu-opioid receptors located in peripheral cancers, such as in lung, breast, and/or colorectal cancer, using opiate radioligands. CRADA Opportunity: The NIEHS Laboratory of Pharmacology, Medicinal Chemistry Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Elizabeth Denholm, Ph.D., Director, NIEHS Office of Technology Transfer, at 919-541-0981 or denholme@mail.nih.gov for more information.

Immunostimulatory Combinations of TLR Ligands and Methods of Use

Sun, 01 Jun 2008 09:00:00 GMT

New drugs or therapies that act by stimulating the immune system, or alternatively inhibiting certain aspects of the immune system, may be useful for treating various diseases or disorders, for example viral diseases, neoplasias, and/ or allergies, and may also have use as vaccine adjuvants. However, although adjuvants have been suggested for use in vaccine compositions, there is an unmet need for adjuvants that can effectively enhance immune response.

Development of innate and adaptive immunity critically depends on the engagement of pattern recognition receptors (PRRs), which specifically detect microbial components named pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs) (1-4). Toll-like receptors (TLRs) represent an important group of PRRs that can sense PAMPs or MAMPs once in the body. TLRs are widely expressed by many types of cells, for example cells in the blood, spleen, lung, muscle and intestines.

The present invention claims immunostimulatory combinations of TLR ligands and therapeutic and/or prophylactic methods that include administering an immunostimulatory combination to a subject. In general, the immunostimulatory combinations can provide an increased immune response compared to other immunostimulatory combinations and/or compositions. More specifically, combinations of TLR 2, 3 and 9 are claimed. The application also describes a novel mechanism for TLR synergy in terms of both signaling pathways and cytokine combinations. CRADA Opportunity: The National Cancer Institute's Vaccine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this invention of synergistic combinations of TLR ligands. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of Amyloid Proteins as Vaccine Scaffolds

Sun, 01 Jun 2008 13:00:00 GMT

Amyloid proteins are composed of peptides whose chemical properties are such that they spontaneously aggregate in vitro or in vivo, assuming parallel or antiparallel beta sheet configurations. Amyloid proteins can arise from peptides which, though differing in primary amino acid sequences, assume the same tertiary and quaternary structures. The amyloid structure presents a regular array of accessible N-termini of the peptide molecules.

Claimed in this application are compositions and methods for use of amyloid proteins as vaccine scaffolds, on which peptide determinants from microorganisms or tumors may be presented to more efficiently generate and produce a sustained neutralizing antibody response to prevent infectious diseases or treat tumors. The inventors have arrayed peptides to be optimally immunogenic on the amyloid protein scaffold by presenting antigen using three different approaches. First, the N-terminal ends of the amyloid forming peptides can be directly modified with the peptide antigen of interest; second, the N-termini of the amyloid forming peptides are modified with a linker to which the peptide antigens of interest are linked; and third, the scaffold amyloid may be modified to create a chimeric molecule.

Aside from stability and enhanced immunogenicity, the major advantages of this approach are the synthetic nature of the vaccine and its low cost. Thus, concerns regarding contamination of vaccines produced from cellular substrates, as are currently employed for some vaccines, are eliminated; the robust stability allows the amyloid based vaccine to be stored at room temperature for prolonged periods of time; and the inexpensive synthetic amino acid starting materials, and their rapid spontaneous aggregation in vitro should provide substantial cost savings over the resource and labor-intensive current vaccine production platforms. CRADA Opportunity: The FDA, Division of Therapeutic Proteins (CDER) and Office of Vaccines, Division of Bacterial Products (CBER) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize amyloid based vaccines for prevention of infectious disease or treatment of malignant states. Please contact Amy Rosenberg at amy.rosenberg@fda.hhs.gov or (301) 827-1794 for more information.

Construction of Recombinant Baculoviruses Carrying the Gene Encoding the Major Capsid Protein, VP1, From Calicivirus Strains (Including Norovirus Strains Toronto, Hawaii, Desert Shield, Snow Mountain, and MD145-12)

Sun, 01 Jun 2008 17:00:00 GMT

The noroviruses (known as "Norwalk-like viruses") are associated with an estimated 23,000,000 cases of acute gastroenteritis in the United States each year. Norovirus illness often occurs in outbreaks, affecting large numbers of individuals, illustrated recently by well-publicized reports of gastroenteritis outbreaks on several recreational cruise ships and in settings such as hospitals and schools. Norovirus disease is clearly important in terms of medical costs and missed workdays, and accumulating data support its emerging recognition as important agents of diarrhea-related morbidity.

Because the noroviruses cannot be propagated by any means in the laboratory, an important strategy in their study is the development of molecular biology-based tools. This invention reports the development of recombinant baculoviruses carrying the capsid gene from several caliciviruses associated with human disease. Growth of these baculovirus recombinants in insect cells results in the expression of virus-like particles (VLPs) that are antigenically indistinguishable from the native calicivirus particle. These VLPs can be purified in large quantities for use as diagnostic reagents and potential vaccine candidates. CRADA Opportunity: The Laboratory of Infectious Diseases, NIAID, NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize norovirus VLP antigens. Please contact Kim Y. Green at kgreen@niaid.nih.gov for more information.

Construction of an Infectious Full-Length cDNA Clone of the Porcine Enteric Calicivirus RNA Genome

Sun, 01 Jun 2008 21:00:00 GMT

Porcine enteric calicivirus (PEC) is a member of the genus Sapovirus in the family Caliciviridae. This virus causes diarrheal illness in pigs, and is presently the only enteric calicivirus that can be grown in cell culture. In addition to its relevance to veterinary medicine as a diarrheal agent in pigs, PEC serves as an important model for the study of enteric caliciviruses that cause diarrhea and that cannot be grown in cell culture (including the noroviruses represented by Norwalk virus). The development of an infectious cDNA clone is important because it enables the use of “reverse genetics” to engineer mutations of interest into the genome of PEC and to study their effects. In addition, it allows the introduction of foreign coding sequences into the genome of PEC that could be useful for vaccine development in swine and possibly humans. This discovery has both basic research applications such as mapping mutations involved in tissue culture adaptation, tissue tropism, and virulence as well as practical applications such as providing a genetic backbone for the development of chimeric vaccine viruses. CRADA Opportunity: The Laboratory of Infectious Diseases, NIAID, NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize reagents derived from an infectious cDNA copy of the genome of porcine enteric calicivirus. Please contact Kim Y. Green at kgreen@niaid.nih.gov for more information.

Enzymatically-Active RNA-Dependent RNA Polymerase From a Human Norovirus (Calicivirus)

Mon, 02 Jun 2008 01:00:00 GMT

The noroviruses (formerly known as “Norwalk-like viruses”) are associated with gastroenteritis outbreaks, affecting large numbers of individuals each year. Emerging data are supporting their increasing recognition as important agents of diarrhea-related morbidity and mortality. The frequency with which noroviruses are associated with gastroenteritis as “food and water-borne pathogens” has led to the inclusion of caliciviruses as Category B Bioterrorism Agents/Diseases. Because the noroviruses cannot be propagated by any means in the laboratory, an important strategy in their study is to development of molecular biology-based tools and replication systems. This invention reports the isolation of the first recombinant, enzymatically-active proteinase and RNA dependent RNA polymerase (RdRp) complex for a human norovirus. This enzyme should facilitate studies aimed at developing therapeutic drugs for norovirus disease. CRADA Opportunity: The Laboratory of Infectious Diseases, NIAID, NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize an active human norovirus proteinase-polymerase enzyme. Please contact Kim Y. Green at kgreen@niaid.nih.gov for more information.

Full-Length cDNA Clone Representing the Consensus Sequence of the RNA Genome of a Human Norovirus (strain MD145-12) That Encodes Biologically Active Proteins

Sun, 01 Jun 2008 05:00:00 GMT

The invention provides for a full-length cloned cDNA copy of the RNA genome of a predominant norovirus strain (Genogroup II.4) designated MD145-12 that was associated with human gastrointestinal illness. The noroviruses, which were formerly known as "Norwalk-like" viruses are estimated to cause 23 million cases of acute gastroenteritis in the USA each year. The virus has been designated into category B of the CDC biodefense-related priority pathogens because it can be used as an agent of bioterrorism. The subject cDNA clone of the virus encodes proteins of the MD145-12 strain that, when expressed in vitro, exhibit properties that would be expected from those produced by the original infectious virus. This cDNA clone is presently the only source to obtain norovirus proteins to facilitate studies aimed at developing control strategies such as vaccines and therapeutic drugs. CRADA Opportunity: The Laboratory of Infectious Diseases, NIAID, NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize reagents derived from a cDNA clone of the genome of a predominant human norovirus strain, Genogroup II.4. Please contact Kim Y. Green at kgreen@niaid.nih.gov for more information.

Muramyl Dipeptide as a Therapeutic Agent for Inflammation

Thu, 01 May 2008 09:00:00 GMT

The nucleotide-binding oligomerization domain 2 (NOD2) protein plays a key role in innate immunity as a sensor of muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan. Bacterial peptidoglycan promotes the innate immune response through the activation of Toll-like receptor 2 (TLR2), which ultimately provokes inflammation. Activation of NOD2 by MDP negatively regulates the activity of TLR2, and thus reduces inflammation.

The inventors have demonstrated that administration of MDP prevents the development of experimental colitis in mice. They have also determined that MDP reduces pro-inflammatory cytokine production from multiple Toll-like receptors, and that this reduction arises from the induction of IFN regulatory factor 4 (IRF4). The technology includes methods of treating or preventing inflammation associated with an autoimmune disorder, particularly inflammatory bowel disease, via administration of muramyl peptide; also included are methods of reducing symptoms characteristic of inflammation via administration of muramyl peptide. CRADA Opportunity: The NIAID Laboratory of Host Defenses, Mucosal Immunity Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact either Rosemary Walsh or Charles Rainwater at 301-496-2644 for more information.

Telomerase Suppressor Compositions and Methods for Diagnosis and Treatment of Cancer

Thu, 01 May 2008 13:00:00 GMT

Lung cancer is responsible for one-third of all cancer related deaths. Although tobacco smoking is a major cause of lung cancer, epidemiological studies have provided evidence for the involvement of genetic factors in the disease onset. For now there are no reliable markers for the early lung cancer diagnostics and no effective treatment except resection of the tumor on early stages. As a result, it is difficult to diagnose lung cancer without invasive methods and before significant progression of the disease has occurred.

NIH inventors have have recently discovered that a gene called CCDC36 (LELA1) is frequently inactivated in patients with non-small cell lung cancer (NSCLC). In many instances of lung cancer, particularly early onset NSCLC, one copy of CCDC36 will be lost due to the chromosomal deletion while the other will be inactivated by promoter methylation. This results in reduction or loss of CCDC36 gene expression. In addition, several single nucleotide polymorphisms (SNPs) found in the gene appeared to be associated with the early onset NSCLC. CCDC36 gene replacement could be utilized as a potential therapeutic strategy. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Human Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "Unique Genetic Changes in CCDC36 Gene That Are Associated with Early Onset Lung Cancer." Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method of Inhibiting ABCG2 and Related Treatments

Thu, 01 May 2008 17:00:00 GMT

The technology is directed to a method of inhibiting ABCG2, which is a multidrug resistance (MDR) protein. It is believed that ABCG2 plays a role in the development of resistance of cancer cells to chemotherapeutics. Therefore, inhibition of ABCG2 would allow chemotherapeutics to be more effective in killing cancer cells, thereby treating cancer. Five compounds were identified in the provisional application that inhibit ABCG2. These compounds are known in the literature and are part of the NCI Developmental Therapeutics Program (DTP). CRADA Opportunity: The National Cancer Institute Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Method of Inhibiting ABCG2 and Related Treatments. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Inhibition of Cell Motility, Angiogenesis and Metastasis

Thu, 01 May 2008 21:00:00 GMT

The present invention relates to potent, highly selective antagonists of Grb2 Src homology-2 (SH2) domain binding. Grb2, through its SH2 domain, mediates growth factor driven cell motility in vitro and angiogenesis in vivo. These synthetic, small molecule antagonists have been shown to block cell motility stimulated by hepatocyte growth factor (HGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial cell growth factor (VEGF). They also potently inhibit HGF- and VEGF-stimulated morphogenesis and angiogenesis, respectively, in several model systems. HGF stimulates mitogenesis, motogenesis and morphogenesis in a wide range of cellular targets during development and adulthood, and its signaling pathway is frequently over-activated in human cancers, including colon, gastric, breast, lung, thyroid and renal carcinomas, melanoma, several sarcomas as well as glioblastoma. The ability of HGF to initiate a program of cell dissociation and increased cell motility coupled with increased protease production promotes aggressive cellular invasion and is frequently linked to tumor metastasis.

Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates. The small, synthetic Grb2 SH2 domain antagonists described in this invention have been shown to inhibit the induced and spontaneous metastasis of melanoma- and prostate cancer-derived tumor cells in mice. These results establish a critical role for Grb2 SH2 domain-mediated interactions in the metastatic process and support the potential efficacy of this class of compound in reducing the metastatic spread of primary solid tumors in humans. CRADA Opportunity: The Urologic Oncology Branch of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Grb2 SH2 domain antagonsists as anti-cancer drugs. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

C4'-Substituted-2-Deoxyadenosine Analogs and Methods of Treating HIV

Fri, 02 May 2008 01:00:00 GMT

The invention describes a new use for C4'-methyl-2-dexoyadenosine, a nucleoside analog that has significant activity against HIV-1 and most strains of HIV previously shown to be resistant to other reverse transcriptase nucleoside inhibitor treatments. In vitro experimental results show substantial anti-HIV activity (blocked infectivity) with no observable cytotoxicity in cell culture. Mechanistic studies indicate that this compound blocks DNA synthesis by reverse transcriptase. CRADA Opportunity: The National Cancer Institute HIV Drug Resistance Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize C4' methyl- and C4'-ethyl-substituted-2-deoxyadenosine analogs Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Novel Growth Factor and Anti-Apoptotic Agent for Promoting Lung Development and Treating Lung Disease

Thu, 01 May 2008 05:00:00 GMT

This invention discloses the novel use of the uteroglobin-related protein 1 (UGRP1), also known as secretoglobin family 3A member 2 (SCGB3A2), as a cell proliferative and anti-apoptotic agent that can be used to promote lung development and treat lung disease. SCGB3A2 is a member of the uteroglobin/Clara cell secretory protein or Secretoglobin gene superfamily of secretory proteins that is normally expressed in the epithelial cells of the trachea, bronchus, and bronchioles, and is known for its anti-inflammatory activity. NIH scientists have, however, recently discovered the surprising growth factor and anti-apoptotic activities of SCGB3A2. These activities allow SCGB3A2 to be used to prevent the development of neonatal respiratory distress, promote lung development, and inhibit the lung damage that results from treatment with certain anti-cancer agents such as bleomycin.

SCGB3A2 administration ex vivo and in vivo was shown to enhance cell proliferation and branching morphogenesis. SCGB3A2 was also shown to suppress or repair bleomycin induced DNA damage/fibrosis when given before, or together with bleomycin treatment in in vitro organ culture, and in an in vivo mouse model of pulmonary fibrosis. These cell proliferative and morphogenic effects of SCGB3A2 make it an attractive candidate for therapeutic use in the treatment of several lung diseases that involve tissue injury or inflammation, such as, pulmonary fibrosis, interstitial pneumonia, emphysema and cancer. SCGB3A2 therapy is also envisioned for use as a lung development agent in premature newborn infants born with underdeveloped lungs. CRADA Opportunity: The National Cancer Institute, Laboratory of Metabolism is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize SCGB3A2 as a clinical tool to treat and/or prevent lung diseases and/or damage caused by various insults including use of the chemotherapeutic agent bleomycin. Lung diseases include pulmonary fibrosis, interstitial pneumonia, emphysema and cancer. We would like to evaluate the effect of SCGB3A2 on the development of emphysema in a smoking model mouse, and as a means to attenuate the severity of all aforementioned diseases in larger animals such as lamb, goat and monkey. We also would like to evaluate the effect of SCGB3A2 on lung maturation using pregnant larger animals. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Three-Dimensional Co-Culture Assay System for Angiogenesis and Metastasis

Thu, 01 May 2008 09:00:00 GMT

This technology features an assay for the detection and measurement of angiogenesis (formation of new blood vessels) and metastasis (spread of cancer). The inventors have developed a three-dimensional co-culture system that closely mimics the in vivo environment in which angiogenesis and metastatic tumors develop. The co-culture system consists of cancerous cells (tumor spheroid or biopsy), endothelial cells, and a combination of other mammalian cells (mast cells, adipocytes, fibroblasts, macrophages, etc.). The cancerous cells can be obtained from cell lines or biopsied tumors from various cancers, such as melanoma, ovarian cancer, hepatocellular cancer, or colon cancer. Cells in the three-dimensional co-culture system express a fluorescent protein having a different emission spectrum. Consequently, the co-culture systems can be used to identify, monitor, and measure changes in morphology, migration, proliferation and apoptosis of cells involved in angiogenesis and/or metastasis. The co-cultures are developed in 96-well plates to allow rapid and efficient screening for whether a drug impacts multiple cell types, modulates angiogenesis and/or has a therapeutic impact on metastasis. This technology not only represents an important tool for angiogenesis and cancer research, but also may be developed into a diagnostic test that allows the development of personalized therapies for cancer and other angiogenesis-mediated disease. CRADA Opportunity: We are very interested in setting up collaborations with pharmaceutical, biomedical, or academic investigators to use our technology in the form of a CRADA or joint grant submission (e.g. DOD). These studies could include expanding the complexity of a 3D co-culture by increasing the partner cell number – paralleling the current model of in vivo angiogenesis. Our existing co-culture assay incorporates both immortalized tumor and endothelial cells. However, other anatomically distinct cells could be added (e.g. pericytes, inflammatory cells [mast cell or macrophages], or fibroblasts) to more accurately mimic the in vivo setting. In addition, a more thorough analysis of our prior xenograft biopsy studies for assessing drug sensitivity could be done using a variety of human tumor cell lines that include lung, colon, breast, prostate, and ovarian cancer. Finally, this collaboration would segue into clinical studies taking biopsy material from cancer patients (following approved IRB protocols) to evaluate anti-angiogenic drug sensitivities to determine the most appropriate FDA reviewed/certified anti-cancer drugs.

The National Cancer Institute, Radiation Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology as noted above. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Microarray Binding Sensors Using Carbon Nanotube Transistors

Thu, 01 May 2008 13:00:00 GMT

Available for licensing and commercial development are: a) an apparatus containing microarray binding sensors having biological probe materials and carbon nanotube transistors (CNTs) and b) various methods of using the highly sensitive CNTs for the electronic detection of nucleic acid hybridization for performing microarray gene expression experiments and detection of DNA-DNA, DNA-RNA, Peptide Nucleic Acid (PNA) -DNA, PNA-RNA, DNA-protein or PNA-protein binding. By analogy to the microarray concept, each transistor is associated with a distinct probe oligonucleotide. Each transistor is operated as a field effect transistor (FET) and the transconductance between the source and drain electrodes is measured before and after a hybridization event. The expected advantages are, besides higher sensitivity and ease of use, the elimination of chemical labeling and enzymatic manipulation and the further miniaturization. The unique distinction of this design over other CNT based biomolecular sensing schemes is the complete isolation of the CNTs from chemical reactions concomitant with probe immobilization and target capture, and the CNTs functioning only as charge sensors. In contrast, current methods rely on enzymatic amplification of nucleic acids, fluorescent labeled targets, hybridization, amplification of signal and detection by optical scanners, which are time consuming and have limited sensitivity. CRADA Opportunity: The Oncogenomics Section, Center for Cancer Research, National Cancer Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize electrical detection of nucleic acid and protein levels. Please contact Javed Khan, M.D. at 301-435-2937 or khanjav@mail.nih.gov for more information.

A Molecular Grading System for Ductal Carcinoma In Situ (DCIS) of the Breast: A New Molecular Diagnostics to Determine Disease Stages of DCIS

Thu, 01 May 2008 17:00:00 GMT

The technology describes the comprehensive profiling of Ductal Carcinoma in situ (DCIS) in breast cancer patients. The inventors have developed a molecular grading system for DCIS utilizing both gene expression profiling and genomic change profiling. The inventors have identified molecular profiles that identify early stage patients at risk of disease progression requiring more aggressive therapy. These observations suggest that a clinical assay could be developed for the grading of DCIS. Furthermore, the invention demonstrates that the profiles correlate with the molecular grade and with cell proliferation, suggesting that a clinical assay using routine methods, based on the nuclear grade and staining for Ki67 as a measure of proliferation, could also potentially be developed. CRADA Opportunity: The National Cancer Institue, Genetics Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize molecular grading of DCIS. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Human Monoclonal Antibody Against Mesothelin

Thu, 01 May 2008 21:00:00 GMT

Mesothelin is a cell surface protein that is naturally expressed at very low levels. However, the expression of mesothelin is significantly increased in aggressive tumors, such as mesotheliomas and pancreatic and ovarian tumors. As a result, mesothelin is an excellent candidate for tumor targeted immunotherapeutics.

Currently, the only antibodies against mesothelin that are available for clinical trials are of murine origin. These antibodies have the potential to elicit immune responses in patients, which may adversely affect the ability to provide patients with repeated doses. As a result, the clinical application of the antibodies may be limited.

In order to address the issue of immunogenicity in patients, NIH inventors have generated an anti-mesothelin antibody of human origin. The antibody has the ability to efficiently recognize mesothelin on the surface of cells, and induce ADCC in mesothelin-positive cells. Thus, this antibody represents an attractive alternative to the murine anti-mesothelin antibodies currently available. CRADA Opportunity: The NCI CCR Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the antibody. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Human and Improved Murine Monoclonal Antibodies Against CD22

Fri, 02 May 2008 01:00:00 GMT

CD22 is a cell surface protein that is highly expressed in a number of B cell lymphomas, such as hairy cell leukemia (HCL), non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Several clinical trials using anti-CD22 antibodies are ongoing. However, all of these antibodies are murine in nature, and have the potential to elicit immune responses in patients. The immunogenicity may adversely affect the ability to provide patients with repeated doses of a therapeutic comprising the antibody, limiting the clinical application of those therapeutics.

In order to address the issue of immunogenicity in a patient, NIH inventors have generated two anti-CD22 antibodies of human origin. Each antibody has the ability to recognize CD22 on the surface of Raji cells. Thus, these antibodies represent an attractive alternative to the murine anti-CD22 antibodies currently being tested in clinical trials.

Additionally, the inventors have generated a modified murine anti-CD22 antibody with increased binding affinity and solubility. This antibody could also be a suitable alternative for the murine antibodies currently available. CRADA Opportunity: The NCI CCR Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-CD22 human monoclonal antibodies. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Human Papillomavirus microRNA Diagnostics and Therapeutics

Thu, 01 May 2008 05:00:00 GMT

Available for licensing and commercial development are patent rights that cover the uses of a p53 specific microRNA (miRNA). It has been reported that the tumor suppressive mRNA miR-34a (a downstream target of p53) is downregulated in HPV-infected primary keratinocytes. miR-34a arrests the cell cycle at G2 phase and promotes apoptosis. Therapeutic restoration of normal expression levels of miR-34a and/or simultaneous stabilization of p53 (inhibited by HPV E6) induces miR-34a accumulation in G0/G1 phase and can arrest tumor growth. Neoplasia and cancer cell progression has also been associated with p18Ink4c overexpression which can be regulated with the introduction of a therapeutic amount of miR-34a. Tumor reduction/suppression by down regulating p18Ink4c is also a therapeutic benefit provided by this invention. CRADA Opportunity: The National Cancer Institute HIV and AIDS Malignancy Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HPV-induced aberrant expression of microRNAs for cervical cancer diagnostics and therapeutics. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Treatment and Diagnosis of Cancer, Diabetes and other Disorders Using Adrenomedullin Peptides and Antibodies

Thu, 01 May 2008 09:00:00 GMT

Adrenomedullin (AM), a 52-amino acid regulatory peptide, is expressed in a wide range of tissues, and has a variety of biological roles. AM was initially identified as a vasodilator, and the effects of AM and its fragments in the cardiovascular system have been widely studied. AM also has important effects on renal function, cell growth, glucose metabolism, and regulation of hormone secretion, and has antimicrobial activity.

This technology claims AM peptides and antibodies, which would be useful in the development of a therapeutic or for diagnostics use. Also claimed are methods of inhibiting tumor cell growth using AM peptides, in particular in a patient suffering from a lung tumor. Claims are also directed to methods of treating a subject with AM-associated conditions, including diabetes, pregnancy, neurological disease, inflammation, or bone development. Finally, methods are claimed for diagnosing or monitoring a disease where AM levels are altered.

Also available is a murine monoclonal antibody, MoAb-G6, which was raised against an AM peptide. This antibody neutralizes AM bioactivity, and reacts with the processed form of AM, but not the preprohormone. This antibody would be useful not only for research use, but also as part of a diagnostic assay for measurement or detection of AM. CRADA Opportunity: The National Cancer Institute Angiogenesis Core Facility is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Use of Adrenomedullin Peptides and Antibodies in the Treatment and Diagnosis of Cancer, Diabetes and other Disorders. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Identification of a Cell-Surface Co-Receptor that Mediates the Uptake and Immunostimulatory Activity of “D” Type CpG Oligonucleotides

Tue, 01 Apr 2008 13:00:00 GMT

Unmethylated CpG motifs are present at high frequency in bacterial DNA. They provide a danger signal to the mammalian immune system that triggers a protective immune response characterized by the production of Th1 and proinflammatory cytokines and chemokines. Although the recognition of CpG DNA by B cells and plasmacytoid dendritic cells is mediated by TLR 9, these cell types differ in their ability to bind and respond to structurally distinct classes of CpG oligonucleotides. The inventors’ work established that CXCL16, a membrane-bound scavenger receptor, influences the uptake, subcellular localization, and cytokine profile induced by D oligonucleotides.

Knowing that CXCL16 can be used to selectively internalize ODN could be useful for (1) improving the activity of D type ODN, (2) improving recognition (and side effects) of other types of ODNs by deleting regions that interact with CXCL16, (3) potentially improving the targeting of any drug or biologic to CXCL16 expressing cells, (4) targeting antisense ODNs to immune cells or preventing side effects from antisense therapy, and also applications to (5) DNA vaccines and other agents that require targeting to CXCL16 expressing cells such as dendritic cells and monocytes.

This application claims methods of inducing an immune response that include administering agents that increase the activity and/or expression of CXCL16 and a D ODN. The application also claims methods of decreasing an immune response to a CpG ODN, including administering agents that decrease the activity and/or expression of CXCL16. Compositions including one or more D type ODNs and an agent that modulates the activity and/or expression of CXCL16 are also claimed. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Immunology, Immune Modulation Group, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Engineered Human Antibody Constant Domains (Nanoantibodies) as Scaffolds for Binders

Tue, 01 Apr 2008 17:00:00 GMT

The invention describes conceptually novel scaffolds based on engineered human antibody constant domains (nanoantibody scaffold). They are highly soluble, very stable, monomeric, and can be expressed at high levels. Furthermore, large libraries are generated from which binders to antigens are selected and characterized. CRADA Opportunity: The National Cancer Institute Center for Cancer Research Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize nanoantibodies as therapeutics or diagnostics including imaging agents. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

HPV Virus-Like Particles for Delivery of Gene-Based Vaccines

Tue, 01 Apr 2008 21:00:00 GMT

The invention describes methods of eliciting immune responses and treating disease based on novel vaccine compositions and vaccination strategies employing human papilloma virus (HPV) virus-like particles (VLPs), comprising L1 and L2 proteins. These VLPs have the capacity to incorporate up to 8 kb of DNA into the shell and express only the target antigen. These compositions are effective at eliciting an immune response to the transgene product expressed by the DNA when administered at epithelial surfaces including the mucosa (e.g. nasal or respiratory passages or genital tract) or skin in conjunction with disruption of the epithelial layer. It is typically difficult to elicit an immune response in the genital tract, so this technology overcomes a previous deficiency. Robust B and T cell responses were elicited in mice using the subject technology with representative DNA expressing M/M2 from respiratory syncytial virus (RSV). This technology could be used in a prime-boost vaccination regimen as well to enhance the immune response. CRADA Opportunity: The NIAID/OTD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HPV Virus-Like Particles for Delivery of Gene-Based Vaccines. Please contact either Cecelia Pazman or Barry Buchbinder at 301-496-2644 for more information.

Polypeptides for Eliciting Neutralizing Antibodies Against HIV

Wed, 02 Apr 2008 01:00:00 GMT

The technology describes conjugate polypeptide compositions that are designed to elicit antibody response against HIV. The peptides are conjugates of one gp41 capable of forming a stable coiled-coil structure and another gp41 capable of forming an alpha-helical structure. These structural elements of gp41 were identified as important for playing a role in HIV-1 cell entry. Compositions that elicit neutralizing antibodies against HIV have been elusive to date, but the subject technology may be important in realizing that goal. CRADA Opportunity: The FDA/CBER Laboratory of Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Carol Weiss at carol.weiss@fda.hhs.gov for more information.

Nitrite Adjunctive Therapy to Enhance Efficacy of Reperfusion Therapy for Acute Myocardial Infarction

Sat, 01 Mar 2008 06:00:00 GMT

The treatment of coronary heart disease is a multi-billion dollar market. In the case of acute myocardial infarction (MI), more commonly known as a heart attack, the patient receives a number of diagnostic tests to determine the type and location of the heart damage. Most patients with ST segment elevation are treated with percutaneous coronary intervention (PCI) or thrombolysis. While current therapies, that attempt to reestablish the blood flow and limit ischemia, can be effective, practical delays between symptom presentation and intervention compromise the amount of myocardial salvage. Moreover, the elapsed time prior to PCI is closely related to the clinical outcome. This has resulted in a mortality rate of 7% after MI and nearly all patients suffer from some degree of myocardial necrosis. However, the use of adjunctive pharmacological therapies can improve myocardial salvage following acute percutaneous reperfusion of an acute MI and substantially impact cardiac function.

This technology is a method of using nitrite as an adjunctive therapy to enhance efficacy of reperfusion therapy for acute MI. Evidence suggests that anion nitrite (NO₂^-) is a physiological signaling molecule with roles in intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling, and cytoprotection. In addition, nitrite has the characteristics of an ideal adjunctive therapy that now appears ready for translation to human clinical trials. The benefits of nitrite therapy include (1) significant cardioprotection after prolonged ischemia, (2) simple administration, (3) low dose for pharmacological action, (4) short half-life (5) minimal side effects, (6) low expense, (7) rapid onset of action. Additionally, the therapy utilizes a cardioprotective mechanism that is not dependent on vasodilation or pressure rate changes. The use and dosing protocols of nitrite, as described by this technology, could limit MI and apoptosis in the reperfusion phase of injury and provide a remarkable degree of cardioprotection. CRADA Opportunity: The NHLBI Pulmonary and Vascular Medicine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize nitrite adjunctive therapy to enhance efficacy of reperfusion therapy for acute myocardial infarction. Please contact Dr. Mark Gladwin at 301-435-2310 for more information.

N-Acetyl Mannosamine as a Therapeutic Agent

Sat, 01 Mar 2008 11:00:00 GMT

N-Acetyl Mannosamine is a precursor for the synthesis of sugar molecules known as sialic acids which play an important role in specific biological processes such as cellular adhesion, cellular communication and signal transduction. Lack of sialic acids also play an important role in disease processes such as cancer, inflammation and immunity.

This invention relates to methods of administering N-Acetyl Mannosamine or its derivative (to produce sialic acid in patients who are deficient in the sugar molecule) to treat muscular atrophy including hereditary inclusion body myopathy (HIBM) and distal myopathy with rimmed vacuoles (Nonaka myopathy). Certain kidney conditions such as those arising from hyposialytion of kidney membranes may be treated by this method as well. CRADA Opportunity: The National Human Genome Research Institute, Medical Genetics Branch, Cell Biology of Metabolic Disorders unit is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize N-acetylmannosamine as a therapeutic agent. Please contact Marjan Huizing at 301-402-2797or mhuizing@mail.nih.gov for more information.

VEGF-B as a Therapeutic Agent for Neurodegenerative Disease

Sat, 01 Mar 2008 16:00:00 GMT

This technology identifies vascular endothelial growth factor-B (VEGF-B) as a potent inhibitor of apoptosis in neuronal and other types of cells, and highlights its ability to rescue these cells from apoptosis in the brain and retina. Members of the VEGF family of proteins are noted for their angiogenic and blood vessel permeabilizing abilities. Some members of this family, such as VEGF-A, may promote neurogenesis; however, the neuroprotective effects are accompanied by inherent angiogenic and vessel permeabilizing activities, which make VEGF-A treatment unsuitable for clinical use as neuroprotective agents. The inventor has recently discovered that unlike the other VEGF family members, the neuroprotective effects of VEGF-B are not associated with undesired angiogenesis or increased blood vessel permeability, but rather through inhibiting apoptosis via suppressing the expression of the apoptotic/cell death related genes (1). This discovery, that the use of VEGF-B can protect endangered neurons from death and avoid the undesirable effects associated with other VEGF family members, makes it a promising candidate for the treatment of neurodegenerative and other diseases that involve neuronal impairment and/or excessive apoptosis, such as muscular dystrophy, stroke, brain injury, myocardial infarction, ischemic renal damage, etc.

In-vivo trials have already demonstrated the efficacy of VEGF-B as a therapeutic agent. VEGF-B has shown efficacy in mouse models suffering from optic nerve crush injury (ONC). ONC induces the apoptotic death of retinal ganglion cells (RGCs) in the retina. However, intravitreal administration of a single dose of the VEGF-B protein significantly restored the number of RGCs by 1.7 fold, demonstrating the potential use of the protein in treating degenerative ocular diseases, such as glaucoma. Similar results were obtained when exogenous administration of VEGF-B to the brain cortex was shown to significantly reduce ischemia-induced stroke volume and to protect neurons from apoptosis in the brain. Further, intracerebroventricular injection of VEGF-B in mutant knockout mice lacking the gene for VEGF-B (VEGFB-KO) has caused a complete reversal of neuronal impairment and restored neurogenesis back to normal levels. CRADA Opportunity: The National Eye Institute, NIH, Office of Scientific Director, Unit of Retinal Vascular Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize VEGF-B as a therapeutic agent in treating various types of degenerative (neural, vascular, muscular, etc) diseases, and to study the molecular and cellular mechanisms involved. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Epoxy-guaiane Cancer Inhibitors: New Class of Natural Products Isolated from the African Plant Phyllanthus englerii

Sat, 01 Mar 2008 21:00:00 GMT

The present invention involves the observation of renal selective inhibitory activity by the extracts of the African plant Phyllanthus englerii. Bioassay-guided fractionation of the purified extracts revealed a series of novel chemical entities which are named Englerin A-F. The englerins and their derivatives are useful in the treatment of a number of cancers, particularly renal cancer. The englerins exhibit selective and potent renal cell inhibitory activity in vitro.

These compounds are recoverable in reasonable yield from natural product extracts and are considered to be reasonably tractable for synthetic chemistry schemes. Sufficient supply of several analogs had been extracted from repository samples for identification and initial biological characterization. Subsequent five-dose testing in the NCI60 screening panel indicated and confirmed impressive renal-selective activity. CRADA Opportunity: The National Cancer Institute Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize epoxy-guaiane cancer inhibitors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

HIV Monoclonal Antibodies

Sun, 02 Mar 2008 02:00:00 GMT

This technology describes several hybridomas that produce monoclonal antibodies (mAbs) useful in HIV research applications. The mAbs are specific for either gp41 or gp120. In particular, the hybridomas producing mAbs designated D19, D56, M12, T8 and T24 (all anti-gp120), and T32 and T33 (gp41 specific) were found to be of particular utility. Additional hybridomas expressing mAbs disclosed in the publications may also be available. CRADA Opportunity: The NIAID/DIR/LVD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HIV Monoclonal Antibodies. Please contact either Michael Pizali or Dana Hsu at 301-496-2644 for more information.

Novel Adjuvant Therapy Using TIMP-2 Variants

Sat, 01 Mar 2008 07:00:00 GMT

Angiogenesis inhibitors are drugs that are being used in cancer therapy to block the development of new blood vessels which could potentially cut off a tumor's supply of oxygen and nutrients. This in turn might stop the tumor from growing and spreading to other parts of the body.

Human protein tissue inhibitor of metalloproteinases-2 (TIMP-2) has been shown to inhibit angiogenesis in vivo independent of metalloproteinase inhibition. The inventors have demonstrated that TIMP-2, as well as TIMP-2 variants lacking metalloproteinase inhibitor activity can revert aggressive tumor cell phenotype to a more differentiated state. In addition, TIMP-2 and the TIMP-2 variants also sensitize tumor cells to the induction of apoptosis by cytotoxic drugs (doxorubicin), thereby enhancing their effectiveness. Novel methods of cancer therapy are disclosed using TIMP-2 or TIMP-2 variants that combine the known anti-angiogenic activity of TIMP-2, with direct tumor-differentiating and chemo-sensitizing activity of TIMP-2. CRADA Opportunity: The NCI Laboratory of Extracellular Matrix Pathology, Cell and Cancer Biology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel cancer therapy methods using TIMP-2 variants. Please contact John D. Hewes, Ph.D., at 301-435-3121 or hewesj@mail.nih.gov for more information.

PSM Peptides as Vaccine Targets Against Methicillin-Resistant Staphylococcus aureus

Sat, 01 Mar 2008 12:00:00 GMT

Available for licensing and commercial development are compositions and methods for the treatment and inhibition of Methicillin-resistant Staphylococcus aureus (MRSA), a dangerous human pathogen. The invention concerns immunogenic peptides that can be used to induce protective immunity against MRSA, including phenol-soluble modulin (PSM) peptides.

In addition to the MRSA infections that occur in immunocompromised patients in hospitals, new MRSA strains have recently emerged that can cause severe infections (such as necrotizing fasciitis) or death in otherwise healthy adults. These strains are increasingly involved in community-associated (CA)-MRSA infections, and can be contracted outside of the health care settings. The incidence of CA-MRSA infections is increasing and the majority of infections in patients reporting to emergency departments in the US is now due to CA-MRSA.

The invention describes a class of secreted staphylococcal peptides with an extraordinary ability to recruit, activate, and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. The peptides are encoded by the PSM gene cluster and include PSMalpha1, PSMalpha2, PSMalpha3, and PSMalpha4, all of which activate and subsequently lyse neutrophils. These peptides are produced at especially high levels in CA-MRSA and to a large extent determine their aggressive behavior and ability to cause disease in animal models of infection. Thus, the peptides represent a set of virulence factors of S. aureus that account for the enhanced virulence of CA-MRSA. The identification of these peptides enables the production of vaccines and other preventative and/or therapeutic agents for use in subjects infected with MRSA. CRADA Opportunity: The NIAID Laboratory of Human Bacterial Pathogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact William Ronnenberg at 301-451-3522 or wronnenberg@mail.nih.gov for more information.

Rapid Clostridium botulinum Diagnostic for Food Safety and Biodefense Applications

Sat, 01 Mar 2008 17:00:00 GMT

The urgent need for a rapid diagnostic test capable of detecting all serotypes of C. botulinum is well known. Botulinum neurotoxins (BoNTs) are the most potent biological toxins known and are categorized as category A biodefense agents because of lethality and ease of production. BoNTs are also one of the most deadly agents associated with food poisoning. Current diagnostic methods include clinical observation of symptoms that could be mistaken for other neurological conditions and a mouse protection bioassay that takes as long as four days and has a number of disadvantages. The subject technology utilizes unique PCR primers for the detection of the non-toxin non-hemaglutinin (NTNH) gene of C. botulinum; this gene is highly conserved in all C. botulinum toxin types and subtypes. Thus, samples that contain botulinum can be determined regardless of serotype involved, providing a universal means of diagnosis. Further, the technology describes different PCR primers and flurogenic probes for a BoNT-specific assay. The type-specific assay can be used independently or in conjunction with the universal assay described above. The universal and type-specific assays were successfully used first to identify positively botulinum DNA samples in a test of botulinum and non-botulinum clostridia species then to determine the toxin type. The diagnostic testing described by the subject technology requires less significantly less time than the current gold standard diagnostic tests. CRADA Opportunity: The NIAID is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize “Rapid Clostridium botulinum Diagnostic for Food Safety and Biodefense Applications.” Please contact either Rosemary Walsh or Barry Buchbinder at 301-496-2644 for more information.

Active MRI Compatible and Visible iMRI Catheter

Sat, 01 Mar 2008 22:00:00 GMT

MRI is a promising imaging modality that provides superior soft tissue contrast and multi planar real-time imaging without harmful ionizing radiation for therapeutic procedures. Interventional magnetic resonance imaging (iMRI) has gained important popularity in many fields such as interventional cardiology and radiology, owing to the development of minimally invasive techniques and visible catheters under MRI for conducting MRI-guided procedures and therapies. This invention relates to a novel MRI compatible and active visible catheter for conducting interventional and intraoperative procedures under the guidance of MRI. The catheter features a non conductive transmission line and the use of ultrasonic transducers that transform RF signals to ultrasonic signals for transmitting RF signal to the MRI scanner. The unique design of this catheter overcomes the concern of patient/sample heating (due to the coupling between RF transmission energy and long conductors within catheter) associated with the design of conventional active MRI catheters. CRADA Opportunity: The National Heart, Lung, and Blood Institute, Cardiac Catheterization Lab is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the alternative Active MRI compatible and visible catheters using ultrasonic technology. Please contact Peg Koelble at koelblep@nhlbi.nih.gov for more information.

Eeyarestatins: Novel Deubiquitination Inhibitors for the Treatment of Drug-Resistant Cancers

Sat, 02 Feb 2008 03:00:00 GMT

The ubiquitin-proteasome system has recently been recognized to play a central role in tumor biology. Bortezomib, an inhibitor of the chymotrypsin-like activity of the proteasome, has clinical activity in a variety of hematologic malignancies and is FDA approved for use in Multiple Myeloma and Mantle Cell Lymphoma.

The present invention for the first time describes that Eeyarestatins, a new class of small molecules, are potential anti-cancer agents. The compounds inhibit the deubiquitination of proteins by targeting the deubiquitination enzymes in the protein degradation pathway. More specifically, the inventors have demonstrated that the Eeyarestatins successfully kill different leukemia and lymphoma cell lines as well as leukemia cells isolated from patients with chronic lymphocytic leukemia by inducing the expression of Noxa, a pro-apoptotic member of the Bcl-2 protein family. Additionally, Eeyarestatins are active against cells that are resistant to Bortezomib and thus can be effective against drug-resistant tumors. CRADA Opportunity: The National Institutes of Health laboratories of Dr. Adrian Wiestner (NHLBI) and Dr. Yihong Ye (NIDDK) are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Eeyarestatins. Please contact Dr. Wiestner (301-594-6855, wiestnera@mail.nih.gov) or Dr. Ye (301-594-0845, yihongy@mail.nih.gov) for more information.

An Improved Non Viral System for Tumor Specific Suicide Gene Therapy

Fri, 01 Feb 2008 08:00:00 GMT

Numerous tumor specific promoters have been identified and developed for targeted gene therapy. Survivin promoter activity is upregulated in 75% of tumors, however the activity is specific but low, resulting in sub-optimal suicide gene expression. Combination of survivin promoter with Bax, a proapoptotic gene, previously used in such therapy has demonstrated low efficacy.

Scientists at NCI have made a plasmid construct consisting of survivin promoter driven mutant form of bax that is constitutively active. This construct is more potent than the wild type bax, improving its efficacy several-fold, while, retaining specificity for tumors, as determined by in vitro and in vivo studies.

This new technology does not use CMV or SV-40 promoters, alleviating the need for modifications for commercialization. CRADA Opportunity: The National Cancer Institute Center for Cancer Research Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tumor specific suicide gene therapy using survivin promoter driven mutant bax. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Ribosomal Protein S3 (RPS3), an Essential Component of NF-kappaB is a Novel and Selective Drug Target

Fri, 01 Feb 2008 13:00:00 GMT

NF-kappaB, represented by the p50-p65 heterodimer, is a DNA binding protein complex that has well documented functions in inflammatory or autoimmune diseases. Its potential as a drug target is currently being explored by the pharmaceutical industry.

The present invention describes that ribosomal protein S3 (RPS3) is a novel component of the p65 homodimer and p65-p50 heterodimer DNA binding complex. Experiments confirmed that RPS3 is essential for normal expression of specific NF-kappaB target genes, including key physiological events that require p65. CRADA Opportunity: The NIAID Laboratory of Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Michael Lenardo at 301-496-6754 for more information.

A Fold-Back Diabody Format for Diphtheria Toxin-Based Immunotoxins That Can Increase Binding and Potency

Fri, 01 Feb 2008 18:00:00 GMT

NIH inventors, in collaboration with Scott and White Memorial Hospital inventors, have developed new immunotoxins comprising a mutant diphtheria toxin linked to an anti-prostate specific membrane antigen (PSMA) fold-back diabody. The fold-back diabody construct has a shortened linker region between the heavy and light chains of the antibody variable domain. This construct allows interactions between the longer-linked variable domains while preventing interactions between the shorter-linked variable domains. This results in increased efficiency of epitope recognition and delivery to the appropriate target cells. These immunotoxins can be used for the treatment of cancers that overexpress PMSA, with specific application against prostate cancer. CRADA Opportunity: The National Institute of Mental Health, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-PSMA fold-back immunotoxins. Please contact David Neville by phone at 301-496-6807 or e-mail davidn@mail.nih.gov for more information.

Inhibiting HIV Infection Using Integrin Antagonists

Fri, 01 Feb 2008 23:00:00 GMT

Infection with HIV depletes and impairs CD4 cells, a key component of the immune system. Effective therapies such as highly active antiretroviral therapy (HAART) have focused on preserving CD4 cells. However, long term HAART has significant toxicity associated with it. The current technology describes the use of integrin antagonists as an alternative to treating or preventing HIV infection and replication. Specifically, alpha4 integrin plays a role in directing lymphocytes to the primary site of HIV replication. Inhibition of the interaction of alpha4beta1 or alpha4beta7 with gp120 can therefore be important in the development of effective HIV treatments. CRADA Opportunity: The NIAID Laboratory of Immunoregulation is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. James Arthos at 301-435-2374 for more information.

Collagen-Induced Platelet Aggregation Inhibitor from Mosquito Salivary Glands

Sat, 02 Feb 2008 04:00:00 GMT

Exposed collagen in injured blood vessels provides a substrate for platelets to adhere and aggregate initiating the first step in thrombosis, the formation of blood clots inside a blood vessel. Despite the essential role of platelets in vascular injury, excessive platelet aggregation may also result in thrombotic diseases such as stroke and heart attack.

Available for licensing is a collagen binding protein, named aegyptin, which selectively inhibits collagen-platelet aggregation, but not platelet aggregation induced by other agonists. Collagen initiates recruitment of circulating platelets and triggers platelet activation. Collagen also plays a critical role in angiogenesis. Aegyptin blocks the interaction of collagen with its major ligands, von Willebrand factor, glycoprotein VI (GPVI), and integrin alpha2beta1. These three ligands are of particular importance because von Willebrand factor plays a critical role in tethering platelets to collagen, GPVI is the major signaling platelet receptor, and integrin alpha2beta1 mediates platelet adhesion and contributes to activation. Since these ligands play a critical role in the early stages of thrombus formation, aegyptin represents a potentially highly effective therapeutic that can prevent and treat patients with thrombotic disease. Alternatively, aegyptin is potentially useful in conditions where collagen plays a critical role in angiogenesis or in conditions where excessive deposition of collagen plays a pathological role (e.g., pancreatic carcinoma). CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Malaria and Vector Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the platelet aggregation inhibitor Aegyptin. Please contact Dr. Jose Ribeiro, Head, Vector Biology Section, at 301-496-9389 or jribeiro@niaid.nih.gov for more information.

Chlamydia Vaccine

Fri, 01 Feb 2008 09:00:00 GMT

Chlamydia trachomatis is an obligate intracellular bacterial pathogen that colonizes and infects oculogenital mucosal surfaces. The organism exists as multiple serovariants that infect millions of people worldwide. Ocular infections cause trachoma, a chronic follicular conjunctivitis that results in scarring and blindness. The World Health Organization estimates that 300–500 million people are afflicted by trachoma, making it the most prevalent form of infectious preventable blindness. Urogenital infections are the leading cause of bacterial sexually transmitted disease in both industrialized and developing nations. Moreover, sexually transmitted diseases are risk factors for infertility, the transmission of HIV, and human papilloma virus-induced cervical neoplasia. Control of C. trachomatis infections is an important public health goal. Unexpectedly, however, aggressive infection control measures based on early detection and antibiotic treatment have resulted in an increase in infection rates, most likely by interfering with natural immunity, a concept suggested by studies performed in experimental infection models. Effective management of chlamydial disease will likely require the development of an efficacious vaccine.

This technology claims vaccine compositions that comprise an immunologically effective amount of PmpD protein from C. trachomatis. Also claimed in the application are methods of immunizing individuals against C. trachomatis. PmpD is an antigenically stable pan-neutralizing target that, in theory, would provide protection against all human strains, thus allowing the development of a univalent vaccine that is efficacious against both blinding trachoma and sexually transmitted disease. CRADA Opportunity: The NIAID, Laboratory of Intracellular Parasites, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize PmpD vaccine development. Please contact Harlan D. Caldwell, at hcaldwell@niaid.nih.gov or 406-363-9333 for more information.

Manganese Superoxide Dismutase VAL16ALA Polymorphism Predicts Resistance to Doxorubicin Cancer Therapy

Fri, 01 Feb 2008 14:00:00 GMT

Cancer is the second leading cause of death in the United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. Major drawbacks of the existing cancer therapies are the interindividial differences in the response and the cytotoxic side-effects that are associated with them. Thus, there is a need to develop new therapeutic approaches to optimize treatment and increase patient survival.

This technology describes the identification of a manganese superoxide dismutase (MnSOD) polymorphism as a novel biomarker for the prognosis of doxorubicin therapeutic response in breast cancer patients, wherein a Val16Ala polymorphism of MnSOD is indicative of patient survival. More specifically, patients undergoing doxorubicin combination therapy with Val/Val, Val/Ala, and Ala/Ala genotypes had 95.2%, 79%, and 45.5% survival rates, respectively, in a case study of 70 unselected breast cancer patients. Carriers of the Ala/Ala genotype had a highly significantly poorer breast cancer-specific survival in a multivariate Cox regression analysis than carriers of the Val/Val genotype. This technology can be developed into an assay to screen for breast cancer patients who will be responsive to doxorubicin treatment. Further, as the MnSOD polymorphism is common in the population (15% to 20% of patients have the Ala/Ala genotype), it is a common risk factor for doxorubicin therapy. This technology can potentially be utilized as a screening tool applicable for all cancer types treated with doxorubicin. CRADA Opportunity: The Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize MnSOD genotyping assays to assess a patient’s response to doxorubicin combination therapy. Please contact John D. Hewes, Ph.D., at 301-435-3121 or hewesj@mail.nih.gov for more information.

3D Imaging of Mammalian Cells Using Focused Ion Beam-Secondary Ion Mass Spectrometry (FIB-SIMS)

Tue, 01 Jan 2008 19:00:00 GMT

Available for licensing and commercial development is a new automated approach to cellular imaging that allows 3D visualization of cellular organelles and protein expression at nanometer (nm) resolution using ion abrasion scanning electron microscopy (IA-SEM). The approach uses established technologies for 3D imaging [1,2] by iterative use of a focused ion beam and scanning electron beam combined with established technologies for mass spectrometry. Strategies to explore the 3D distribution of cellular components are being developed with the goal of establishing rapid methods for determining protein, metabolite and drug localization in the subcellular space. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research and/or partnership agreements to further develop and commercialize tools for 3D mapping cells and tissues at nanometer resolution. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Diagnosis and Treatment of Barrett's Esophagus and Associated Esophageal Adenocarcinoma

Wed, 02 Jan 2008 00:00:00 GMT

Barrett's esophagus is a condition in which the normal esophageal tissue lining has been replaced by an abnormal lining of gastric and intestinal tissue resulting from chronic gastroesophageal reflux disease. Patients have an increased risk of developing esophageal adenocarcinoma, which is often detected at later stages and is associated with poor prognosis. Survival rates are very low ranging from 10% in Europe to 16% in the United States.

Available for licensing are microRNA (miRNA) biomarkers that show differential expression in the adenocarcinoma diagnosis and Barrett's esophagus status, and they can predict diagnosis and Barrett's esophagus with accuracies of 71.4% and 74.7%, respectively. Thus, these miRNA biomarkers that may predispose individuals to Barrett's esophagus and/or esophageal adenocarcinoma could provide a means for earlier detection and help in better identifying treatment options. CRADA Opportunity: The Laboratory of Human Carcinogenesis at the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods to diagnose and treat Barrett's esophagus and esophageal carcinoma. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Method of Immunizing Humans Against Salmonella typhi Using a Vi-rEPA Conjugate Vaccine

Tue, 01 Jan 2008 05:00:00 GMT

This invention is a method of immunization against typhoid fever using a conjugate vaccine comprising the capsular polysaccharide of Salmonella typhi, Vi, conjugated through an adipic dihydrazide linker to nontoxic recombinant exoprotein A (rEPA) from Pseudomonas aeruginosa. The three licensed vaccines against typhoid fever, attenuated S. typhi Ty21a, killed whole cell vaccines and Vi polysaccharide, have limited efficacy, in particular for children under 5 years of age, which make an improved vaccine desirable.

It is generally recognized that an effective vaccine against Salmonella typhi is one that increases serum anti-Vi IgG eight-fold six weeks after immunization. The conjugate vaccine of the invention increases anti-Vi IgG, 48-fold, 252-fold and 400-fold in adults, in 5-14 years-old and 2-4 years-old children, respectively. Thus this is a highly effective vaccine suitable for children and should find utility in endemic regions and as a traveler's vaccine. The route of administration can also be combined with routine immunization. In 2-5 years old, the protection against typhoid fever is 90% for 4 years. In school age children and in adults the protection could mount to completer protection according to the immunogenicity data. hewesj@mail.nih.gov for more information.

Micropatterning of Extracellular Matrix Proteins Using Microphoto-ablation Of Poly vinyl Alcohol (PVA) Monolayers

Sat, 01 Dec 2007 10:00:00 GMT
Available for licensure and commercial development is a micro-photoablation (µPA) method used as a micro-patterning technique to attach ECM proteins or other biological molecules to specified locations. Advantages of this photolytic technique are that it: (a) is stampless, (b) allows for flexible pattern generation to the submicron level, (c) allows for live cell fluorescence imaging, retains cell viability, and (d) allows the use of multiple proteins. The technique has demonstrated experimentally that micropatterning with live cell fluorescence imaging can be used to precisely visualize studying distinct cell-ECM interactions.

Applications of microlithography techniques into the study of cell biology aid in resolving cellular function as regulated by the interaction of cells with the extracellular matrix. Currently many techniques have used micro-contact patterning (µCP) to apply ECM proteins in distinct localized patterns. These techniques require the fabrication of silicone-based stamps to either "ink" proteins directly or indirectly onto a gold coated surface, limiting the user to a specified stamp shape and size. To bypass the necessity of a physical stamp the current technique provides submicron sized spots using a tunable multiphoton laser coupled to a confocal microscope to photo ablate hydrophilic poly vinyl alcohol (PVA) macro-molecular thin films. Through controlled photo ablation, PVA layers are locally removed allowing deposition of ECM proteins into distinct patterns. The use of ROI's produces a "virtual mask" that can be created in any shape or pattern and are easily modified. Unlike µCP techniques, micro-photoablation (µPA) allows live cell imaging of multiple fluorophores and is possible even with total internal reflection fluorescence (TIRF) microscopy. Therefore, micro-photo ablation (µPA) allows kinetic quantification of ECM-cell interactions. This technique that uses a macro-molecular thin film together with localized photo ablation allows the versatility to create protein spots of any size or shape easily on the same cover slip. Furthermore, this process can be repeated multiple times to directly conjugate different proteins to the same local region allowing the investigation of how single cells probe their surroundings to discern different ECM proteins. CRADA Opportunity: The National Institute of Dental and Craniofacial Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Microphoto-ablation Of Poly vinyl Alcohol (PVA) Monolayers. Please contact David W. Bradley, Ph.D. at bradleyda@nidcr.nih.gov for more information.

Quantitative Determination Of Marker Proteins In Complex Mixtures

Sat, 01 Dec 2007 15:00:00 GMT
The Laboratory of Neurotoxicology of the National Institute of Mental Health and the Laboratory of Cell Biology of the National Cancer Institute are seeking statements of capability or interest from parties interested in forming a collaborative research alliance to further develop, evaluate, or commercialize techniques for protein quantification using mass spectrometry. This technology can be used in basic research, disease diagnosis or treatment to determine absolute and stoichiometric amounts of specific marker proteins in heterogeneous mixtures such as blood or urine.

High throughput methods have already been devised to purify cellular complexes from well-established cell models such as yeast using protein tags. Current techniques for protein quantification that utilize mass spectrometry depend on the quantification of peptides generated during proteolytic digestion. Chemical labeling of peptides after digestion or metabolic labeling of growing cells in the presence of labeled substrate are useful for relative analyses of different sample groups. Chemical synthesis of isotopically-labeled peptides has inherent limitations that may restrict proteotypic peptide selection, although complications have been circumvented by using a synthetic gene to code for a protein expressing a concatenated series of proteotypic peptides within a synthetic standard fusion protein. The approach was refined by incorporating flanking sequences into the fusion protein to account for sequence difference effects on proteolytic efficiency.

This technology utilizes a combination of recombinant DNA technology, fluorescence, proteolytic and mass spectrometric methods. The technique uses the identities of components known to be present in the mixture to construct and purify fusion proteins containing each of the proteins in the mixture fused to a protein exhibiting native fluorescence. CRADA Opportunity: The National Cancer Institute, Laboratory of Cell Biology and the National Institute of Mental Health, Laboratory of Neurotoxicology are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostics that utilize protein quantification that utilize mass spectrometry. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Nanoparticles For Imaging: Targeted Nanoparticles That Can Be Imaged Through Magnetic Resonance, Optical, And Radioisotope Imaging

Sat, 01 Dec 2007 20:00:00 GMT
Available for licensing and commercial development are patent rights covering tri-imageable nanoparticles which have great potential for application in the laboratory and clinic for labeling at the cellular level, diagnostics, and drug delivery. The particle includes a silica encased ultrasmall superparamagnetic iron oxide (SPIONs) that can be detected using MRI. A fluorescent probe (e.g., Cy5.5) for optical imaging is embedded in the silica. The resulting particles are about 20-25nm in diameter. Target specific antibodies are attached to the surface of the particles. Chelated to the antibodies is a radioisotope (e.g., Indium-111) useful for particle quantification and can be imaged through techniques such as single photon emission computed tomography(SPECT) or positron emission tomography (PET). A graphical representation of an exemplary nanoparticle according to the invention is shown in the accompanying illustration.

CRADA Opportunity: The National Cancer Institute Radiation Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these tri-imageable nanoparticles. Please contact John Hewes, Ph.D., at 301-435-3121 or hewesj@mail.nih.gov for more information.

Tri-functional Imaging Agent for Monoclonal Antibody Tumor-Targeted Imaging

Sun, 02 Dec 2007 01:00:00 GMT
Available for licensing and commercial development is a novel lysine-based trifunctional chelate which bears both a chelating moiety (CHX-A") for sequestering radiometals (⁸⁶Y or ¹¹¹In) and a near-infrared dye, e.g., Cy5.5, for dual modality PET (or SPECT) and fluorescence imaging. Successful conjugation of monoclonal antibody trastuzumab (Herceptin) or cetuximab (Erbitux), has also been achieved by efficient thiol-maleimide chemistry, thereby yielding an immunoconjugate (Signaling agent (Cy5.5-Lys(SMCC)-CHX-A") conjugated to trastuzumab) or (Signaling agent (Cy7-Lys(SMCC)-CHX-A") conjugated to cetuximab). Both specifically target antigen expressing cells and internalization of the agent has been imaged over time. Trastuzumab can be radiolabeled with isothiocyanate derivatives of the bifunctional chelating agents 1B4M (2-(4-aminobenzy1)-6-methyldiethylenetriaminepentaacetic acid); and CHX-A" (N-[(R)-2-amino-3-(p-aminophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid). CRADA Opportunity: The National Cancer Institute Radiation Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, Trifunctional Imaging Agent for Monoclonal Antibody Tumor-Targeted Imaging. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

cDNA Encoding a Gene BOG and its Protein Product

Sat, 01 Dec 2007 06:00:00 GMT
Available for licensing is BOG (B5t Over-Expressed Gene) with the gene product pRb of the well-known tumor suppressor gene RB, retinoblastoma susceptibility gene. The complex formed between Rb and BOG typically does not contain E2F-1 in vivo. This binding property suggests that cells which are transformed/transfected with cDNA or other functional nucleotide sequences which encode the BOG gene product will be useful as tools for studying cell cycle control and oncogenesis.

Studies using rat liver epithelial cell (RLE) lines which are resistant to the growth inhibitory effects of TGF-beta1 and primary liver tumors have been shown to over-express BOG. Moreover, when normal RLE continuously over-express BOG the cells become transformed and the transformed cells are able to form hepatoblastoma-like tumors when transplanted into nude mice. Therefore, biologics derived from BOG may be useful as diagnostics or therapeutics. CRADA Opportunity: The National Cancer Institute (NCI), Center for Cancer Research, Laboratory of Experimental Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize of BOG (B5t Over-Expressed Gene) with the gene product pRb. Please contact John Hewes, Ph.D. at the NCI Technology Transfer Center at hewesj@mail.nih.gov or (301) 496-0477 for more information.

SLCO1B3 Genotyping to Predict a Survival Prognosis of Prostate Cancer

Thu, 01 Nov 2007 10:00:00 GMT
Steroid hormones have been implicated in playing a fundamental role in the pathogenesis of prostate cancer. Polymorphisms in the genes that code for enzymes or hormones involved in androgen regulatory pathway are proposed to influence an individual's risk for developing prostate cancer. Since many membrane transporters are modulators of steroid hormones absorption and tissue distribution, genetic polymorphisms in genes encoding these transporters may account for the risk of prostate cancer and the predicting of survival. The OATP1B3 (formerly OATP8) steroid uptake transporter is overexpressed in prostate cancer, and polymorphisms in SLCO1B3 have been associated with altered testosterone uptake, and also an increased prostate cancer risk.

This invention identifies two polymorphic genetic markers in the SLCO1B3 (formerly SLC21A8) gene, called 334T>G and 699G>A, that can be measured in genomic DNA obtained from a blood sample to predict survival from diagnosis of prostate cancer in that individual patient. This genetic profiling result has profound clinical applications in diagnosis for each individual patient and ultimate treatment regimen. Specifically, the inventors have provided a correlation between clinical outcome of SLCOlB3 genotype with median survival of androgen independent prostate cancer. They have also shown that the genotype is predictive of testosterone uptake through the OATP1B3 transporter, and this information is useful to inform clinical decisions regarding antiandrogen therapy. CRADA Opportunity: The National Cancer Institute's Medical Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of the SLCO1B3 genotyping to inform clinical decisions regarding drug treatment, or prognosis of prostate cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Family of Small Molecules for Selective Inhibition of Wip1 Phosphatase

Thu, 01 Nov 2007 14:00:00 GMT
The Wip1 phosphatase acts on proteins containing a particular phosphorylated amino acid sequence. Studies have shown that Wip1 is overexpressed in a number of human cancers, including breast cancer, neuroblastoma and ovarian cancer. Wip1 activity has also been shown to have a suppressive effect on the tumor suppressor p53. This suggested that inhibition of Wip1 could be of therapeutic value in the treatment of cancer.

NIH inventors have developed small molecules that simulate the structure of the amino acid sequence that Wip1 recognizes. The structure of the small molecules allows for specific targeting to Wip1. These small molecules have the ability to significantly inhibit Wip1 phosphatase activity at the micromolar level. As a result, these small molecules can be used in the design of therapeutics for cancers that overexpress Wip1. CRADA Opportunity: The National Cancer Institute’s Laboratory of Cell Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutics for cancers that overexpress Wip1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Clinically Proven Therapeutic Treatment and Diagnostic Tool for Mesothelin Expressing Cancers: A Novel Recombinant Immunotoxin SS1P (anti-mesothelin dsFv-PE38)

Thu, 01 Nov 2007 18:00:00 GMT
Mesothelin is a cell surface glycoprotein, whose expression is largely restricted to mesothelial cells in normal tissues. Mesothelin has been shown to be highly expressed in many cancers including malignant mesothelioma, ovarian cancer, lung cancer, pancreatic carcinomas, gastric carcinomas, and other cancers. Mesothelin has been shown to be a target for immunotherapy and is also being used as a tumor marker.

The technology relates to the SSIP immunotoxin that can be used to kill cells expressing mesothelin on their surface, such as mesothelioma, ovarian cancer, lung cancer, pancreatic cancer and stomach cancer. Additionally, it can be used for the detection of mesothelin expressing cells present in a biological sample.

The SSIP protein is an immunotoxin generated by the fusion of an anti-mesothelin antibody Fv fragment with a particularly high affinity (SS1), and a ~38 kDa portion of Pseudomonas Exotoxin A (PE38). CRADA Opportunity: The National Cancer Institute Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, immunotoxin SS1P. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Monoclonal Antibody to a Specific Peptide-MHC Class II Complex

Thu, 01 Nov 2007 22:00:00 GMT
T lymphocytes play an important role in the immune system by recognizing foreign protein motifs on cells. T lymphocytes are stimulated to recognize these motifs through their interactions with peptide-MHC complexes (pMHC). Thus, studying pMHC is an important aspect of understanding how the immune system works, particularly with regard to the development of vaccines. Unfortunately, the detection of pMHC is largely dependent on indirect assays, due to the difficulty of producing antibodies for specific pMHC.

This invention regards the development of hybridomas (C4H3) for the production of antibodies that are highly specific for a particular pMHC complex consisting of hen egg lysozyme peptide 46-61 (HEL) and the I-A^k MHC class II molecule. These antibodies can be used for a myriad of purposes which include studying how cells form pMHC. CRADA Opportunity: The NIAID Lymphocyte Biology Section, Laboratory of Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize monoclonal antibody C4H3, specific for HEL (46-61) bound to the MHC class II molecule I-A^k. Please contact Ronald N. Germain, M.D., Ph.D. at rgermain@nih.gov for more information.

Diagnostic Ovarian Cancer Biomarkers

Fri, 02 Nov 2007 02:00:00 GMT
Ovarian cancer is one of the most common malignancies. Warning symptoms generally do not occur until the tumor has already spread beyond the ovary. As a result, patients are diagnosed with advanced stages of ovarian cancer and their prognosis is poor. Five year survival rate for these patients is only fifteen percent and despite a clinical response of eighty percent to surgery and chemotherapy, most patients experience tumor recurrence within two years of treatment. The overwhelming majority of patients will eventually develop chemoresistance and lose their battle against cancer.

The inventors have discovered unique proangiogenic biomarkers isolated from ovarian endothelial cells. By targeting tumor angiogenesis by inhibiting endothelial cells that support tumor growth, this technology provides methods to diagnose ovarian cancer in its early stages.

Available for licensing is a gene profile that is indicative of patient survival. Unlike other biomarkers that are determined from discrete patient groups at either end of the survival spectrum, this profile is based upon expressed genes in late stage, high-grade papillary serous ovarian tumors. This predictive patient survival profile is based upon the theory that gene expression for advanced late stage ovarian cancer is more likely to develop aggressive, recurrent disease.

Also available for licensing is a gene signature that can predict whether a patient will respond positively to chemotherapy, show an initial response but will relapse within six months of completing chemotherapy, or not respond to chemotherapy. This methodology may enable clinicians to identify patients who need alternative chemotherapy regiment and to recommend cancer treatment appropriately. CRADA Opportunity: The Cell and Cancer Biology Branch of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a gene expression profile that predicts ovarian cancer patient response to chemotherapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Novel, Inhibitory Platelet Surface Protein (TREM Like Transcript, TLT-1): New Target for the Treatment of Cancer, Infectious Diseases, Cardiac Diseases, and Platelet-Associated Disorders

Thu, 01 Nov 2007 06:00:00 GMT
Triggering Receptors in Myeloid Cells (TREM) recently were discovered to modulate innate and adaptive immunity. Specifically, TREM1 amplifies the response to sepsis in innate immunity by activating neutrophils and other leukocytes; and TREM2 potentiates dendritic cell maturation in adaptive immunity.

This invention describes a novel, inhibitory platelet surface protein known as TREM like Transcript (TLT-1). TLT-1 is the first inhibitory receptor discovered to reside within the TREM gene locus. Structurally, TLT-1 also possesses inhibitory domains that indicate this regulatory function. TLT-1 is highly expressed in peripheral blood platelets and may modulate many other types of myeloid cells. Additionally, the invention describes specific, human, single chain antibodies (scFvs) that recognize TLT-1. CRADA Opportunity: The National Cancer Institute's Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antibodies that react specifically with TLT-1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Human T-box Transcription Factor Brachyury as a Target for Cancer Immunotherapy: Identification of Epitopes of Human Brachyury as Targets for T-cell Mediated Lysis of Tumors

Thu, 01 Nov 2007 10:00:00 GMT
Identification of tumor antigens is essential in advancing immune-based therapeutic interventions in cancer. Transcription factors that control mesoderm have been implicated in tumor cell invasion and metastasis. Brachyury, a member of the T-box transcription factor family, is a highly conserved protein and a fundamental player in mesoderm (epithelial-to-mesenchymal transition, i.e. EMT) specification in multicellular organisms.

This invention describes the identification of the human transcription factor Brachyury as a novel target for cancer immunotherapy for the treatment of several tumors such as tumors of lung, intestine, stomach, kidney, bladder, uterus, ovary, and testis, and chronic lymphocytic leukemia. This is the first demonstration that (a) a T-box transcription factor and (b) a molecule implicated in mesodermal development (EMT) can be a potential target for human T-cell mediated cancer immunotherapy. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Tumor Immunology and Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cancer vaccines aimed at targeting Brachyury. Please contact Kevin Brand, J.D. at 301-451-4566 or kb229t@nih.gov for more information.

Selenocysteine Mediated Hybrid Antibody Molecules

Thu, 01 Nov 2007 14:00:00 GMT
Available for licensing is a new class of hybrid molecules composed of an antibody, or antibody fragment, and a small synthetic molecule (such as a small molecule inhibitor, or cytotoxic compound). These biological and chemical components are covalently linked at an engineered selenocysteine near the C-terminus of the antibody, or antibody fragment. Through this covalent linkage, the chemical and the biological component can acquire properties of one another. For example, the synthetic molecule acquires antibody properties such as circulatory half-life, effector functions, and ability to interfere with protein interactions whereas the antibody, or antibody fragment, acquires properties of the small synthetic molecule such as specificity, affinity, and stability to bind to targets that are sterically inaccessible to immunoglobulins. The technology can also be used to equip an antibody, or antibody fragment, with a small synthetic molecule that enhances target destruction or imaging capabilities through site-selective biotinylation, PEGylation, addition of an imaging agent, or addition of a cytotoxic agent such as a chemotherapeutic drug or a chelate for radioisotope labeling. The hybrid antibody molecules can be engineered with a variety of small synthetic molecules, and the combination of immunogenic properties and those of the small synthetic molecules results in compounds with powerful target destruction or imaging capabilities. This technology could be applied towards the targeted delivery of small synthetic molecules to various cell surface receptors, and may have applicability as a prevention, diagnosis, or therapy for numerous disease states. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Experimental Transplantation and Immunology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Selenocysteine Mediated Hybrid Antibody Molecules. Please contact Dr. Christoph Rader at (301) 451-2235 or raderc@mail.nih.gov for more information.

Inactivation of Enveloped Viruses and Tumor Cells for Infectious Disease and Cancer Vaccines

Thu, 01 Nov 2007 18:00:00 GMT
The current technology describes the inactivation of viruses, parasites, and tumor cells by the hydrophobic photoactivatable compound 1,5-iodoanpthylazide (INA). This non-toxic compound will diffuse into the lipid bilayer of biological membranes and upon irradiation with light will bind to proteins and lipids in this domain, thereby inactivating fusion of enveloped viruses with their corresponding target cells. Furthermore, the selective binding of INA to protein domains in the lipid bilayer preserves the structural integrity and therefore immunogenicity of proteins on the exterior of the inactivated virus. This technology is universally applicable to other microorganisms that are surrounded by biological membranes like parasites and tumor cells. The broad utility of the subject technology has been demonstrated using influenza virus, HIV, SIV, Ebola and equine encephalitis virus (VEE) as representative examples. The inactivation approach for vaccine development presented in this technology provides for a safe, non-infectious formulation for vaccination against the corresponding agent. Vaccination studies demonstrated that mice immunized with INA inactivated influenza, Ebola and VEE mounted a protective immune response against lethal doses of the corresponding virus. CRADA Opportunity: The National Cancer Institute’s Membrane Structure and Function Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize non-infectious formulation for vaccination. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel Micro-RNA Sequence Transforms Non-Functional T-Lymphocytes to Highly Functional: Key to Improved Immunotherapy for the Treatment of Cancers

Mon, 01 Oct 2007 22:00:00 GMT
This technology is directed to the therapeutic use of microRNA-181a in the adoptive immunotherapy of cancer.

The adoptive transfer of anti-tumor T cells after a lymphodepleting regimen can result in the regression of metastatic cancer both in mouse and human, but the production of highly-reactive, tumor-specific T cells still represents a barrier to broad implementation of T cell-based immunotherapies. This technology enables the use of microRNA (miR)-181a, a recently identified intrinsic modulator of T-cell receptor (TCR) signaling, to improve anti-tumor T cell responsiveness. Micro-RNAs are short RNA molecules that regulate the activity of genes and appear to control biological processes.

We found that genetic engineering of T lymphocytes with miR-181a dramatically augmented the function of poorly responsive human tumor-infiltrating lymphocytes and TCR-engineered peripheral blood lymphocytes, resulting in potent anti-tumor reactivity. Furthermore, in a mouse model, miR-181a increased the function of self/tumor-specific CD8+ T cells enabling effective tumor destruction in the absence of vaccination or exogenous cytokines that were otherwise essential requirements. This technology is the first reported use of a miRNA gene as tool in the treatment of disease. CRADA Opportunity: The Surgery Branch of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the therapeutic use of microRNA-181a in the adoptive immunotherapy of cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Fundus Photo-Stimulation System and Method

Tue, 02 Oct 2007 02:00:00 GMT
Available for licensing and commercial development is an optical system which permits targeted photo-stimulation of the retina by positioning the stimulus location under visual guidance through a fundus camera. The system is designed to elicit, under direct infra-red visual control of stimulus size and position in the retina, electroretinograms (ERGs) in response to photo-stimulation from selected regions of the retina, as well as to present small light stimuli to a selected area to explore visual sensitivity properties. For example, the detected ERGs can be the basis for diagnosing or characterizing patient retina with early stage retinal disease versus healthy retina from the opposite eye. The system can be mounted on commercially available fundus cameras that have infra-red capabilities (or would accept infra-red bandpass filtering of their retinal illumination output) and will accept a near IR CCD camera connected to a TV mounted on the photographic-camera port.

The optical system can comprise a targeting light path originating from a deep red laser and a stimulus light path originating from a Xenon strobe lamp. Both light paths are brought into collinear alignment by a beam splitter. The light paths are transmitted to the eye through an adjustable turning mirror and a focusing lens. A beam splitter in front of the fundus camera objective lens merges the optical path of the fundus camera with that of the targeting optical path and the stimulus light path. The merged beams are brought to a focus at or close to the lens of the eye. A movable aperture is interposed on the collinear beams and imaged on the retina such that its lateral position and size can be adjusted by the operator to select the retinal area to be photo-stimulated. This arrangement ensures that the stimulating light flashes illuminate the same field as was selected using the deep red targeting laser. This system permits projection of repeatable visible-light flashes with variable size and location onto the retina. CRADA Opportunity: The Laboratory of Bioengineering and Physical Science, NIBIB is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Fundus Photo-Stimulation System and Method. Please contact Dr. Paul Smith at smithpa@mail.nih.gov for more information.

Optical Slice Motion Tracker

Mon, 01 Oct 2007 06:00:00 GMT
Available for licensing and commercial development is an apparatus that adjusts the focal plane of a microscope in order to track plane motion of a sample. The apparatus includes a motor that can change the focal plane by moving the objective of the microscope and a computer that reads image data from the microscope photomultiplier tube (PMT). The apparatus uses time between images to perform a navigator function comprising quickly scanning many nearby focal planes with a minimum field of view and utilizing pattern matching to calculate an offset distance to adjust the focal plane. The apparatus permits imaging of moving structures, such as living tissue, over time by compensating for motion in the direction of the focal plane. The use of navigator movement to track an optically selected slice can be implemented in any of various research or medical devices. CRADA Opportunity: The NHLBI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the optical slice motion tracker. Please contact Lili Portilla at 301-594-4273 or via email at Lilip@nih.gov for more information.

HIV-1 Integrase Inhibitors for the Treatment of Retroviral Infections

Mon, 01 Oct 2007 10:00:00 GMT
This technology describes the structure and activity of N-benzyl derivatives of 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 2,3-dihydro-6,7-dihydroxy-1H-isoindole-1,3(2H)-diones as new HIV-1 integrase inhibitors. HIV, as well as other retroviruses, requires three key viral enzymes for replication: Reverse transcriptase, protease and integrase (IN). A significant number of patients fail to respond to combination therapies consisting of reverse transcriptase and protease inhibitors, due to the development of viral resistance. IN functions by initial processing of viral cDNA in a cleavage step termed 3’-processing (3’-P). This is followed by insertion of the cleaved cDNA into the host genome in a reaction known as “strand transfer” (ST). Certain agents covered under the subject technology have been shown to exhibit selective inhibition of ST reactions relative to 3’-P reactions. These compounds inhibit purified IN in vitro and are also active against HIV-1 derived vectors in cell-based assay. These inhibitors may have a potential therapeutic value for retroviral infections, including AIDS, especially for patients exhibiting drug resistant to current therapy regimes. CRADA Opportunity: The National Cancer Institute's Laboratory of Medicinal Chemistry and Laboratory of Molecular Pharmacology are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the HIV-1 integrase inhibitors described. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Predictive Diagnostic Test for Anti-Depressant Related Suicide Risk

Mon, 01 Oct 2007 14:00:00 GMT
A number of studies have reported a potential link between antidepressant treatment and suicides. Although the scientific basis for this phenomenon is not known, the Food and Drug Administration (FDA) required a black box warning of worsening depression and/or emergence of suicidality (i.e., development of suicidal thoughts or behavior) in both adult and pediatric patients taking several antidepressants. While use of antidepressants fell subsequent to the black box warning, recent studies suggest that pediatric suicides may actually be rising. This has led to concerns that untreated depression due to the black box warning could potentially result in an overall increase in suicides.

To determine whether a genetic basis for suicidal risk exists for a sub-group of depressed patients, NIH researchers genetically screened patients with major depression treated with the serotonin selective reuptake inhibitor (SSRI) citalopram (Celexa) in the NIMH-funded Sequenced Treatment Alternatives for Depression (STAR*D) trial. Versions of two genes coding for components of the brain's glutamate chemical messenger system were linked to suicidal thinking associated with antidepressant use. Having both implicated versions increased risk of such thoughts more than 14-fold. By identifying those patients who need close monitoring, alternative treatments and/or specialty care, these genetic tests should prevent the under prescribing of anti-depressant drugs and the resulting possibility of suicide due to sub-optimal treatment. CRADA Opportunity: The National Institute of Mental Health Mood and Anxiety Disorders Program Genetics Unit is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Predictive Diagnostic Test for Anti-Depressant Related Suicide. Please contact Dr. Francis McMahon at mcmahonf@mail.nih.gov for more information.

Novel Roles of a DNA Repair Protein, DNA-PKcs, in Obesity, Neurological Function, and Aging

Mon, 01 Oct 2007 18:00:00 GMT
The catalytic subunit of the DNA-dependent protein kinase complex (DNA-PKcs) has been shown to be important in DNA repair and VDJ recombination in lymphocytes. The inventors have discovered that DNA-PKcs also plays novel, important roles in energy regulation and neurological function. The inventors observed that mature DNA-PKcs-deficient mice (also known as SCID mice) have a lower proportion of fat, resist obesity, and have significantly greater physical endurance than wild-type control mice, particularly with increasing age. The inventors also observed that DNA-PKcs-deficient mice have better memory and less anxiety. One potential explanation for this is that they express higher levels of brain-derived neurotrophic factor (BDNF), which is associated with neurogenesis, memory formation and suppression of anxiety and depression. Moreover, DNA-PKcs-deficient cells produce less oxidative stress. Thus, inhibition of DNA-PKcs may have unexpected utility in the treatment of a wide range of diseases and conditions.

The invention discloses methods of inhibiting DNA-PKcs activity to decrease adiposity, improve physical endurance and increase insulin sensitivity and the number of mitochondria. Also claimed are methods directed to improved neurological function, such as methods for protection from neurodegenerative disease, improving memory and learning ability, and for reducing depression and anxiety. Additionally, the invention discloses methods for reducing inflammation and for treating heart disease. CRADA Opportunity: The National Heart Lung and Blood Institute, Laboratory of Biochemical Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize DNA-PKcs inhibitors for treatment or prevention of metabolic and degenerative diseases. Please contact Jay Chung (chungj@nhlbi.nih.gov) for more information.

Flexible, Polyvalent Antiviral Dendritic Conjugates for the Treatment of HIV/AIDS

Mon, 01 Oct 2007 22:00:00 GMT
This technology describes the design and synthesis of flexible, polyvalent, antiviral conjugates of less than 200 kDa for the treatment HIV/AIDS. These conjugates are mimetic of D1D2-Igatp, a high-molecular-weight (1 MDa) CD4-immunoglobulin fusion construct with extreme HIV neutralizing potency. Cryo electron microscopy suggests that the extreme potency of D1D2-Igatp is due to polyvalent presentation of a gp120-binding ligand on a flexible scaffold. The current prototype for the technology is a conjugate comprising soluble, two-domain human CD4 covalently linked to a flexible poly(ethylene glycol)-PAMAM dendrimer scaffold. The construct is designed to retain a high degree of flexibility and polyvalence, and, at less than 200 kDa, is similar in size to successful antibody therapeutics currently on the market. Because it retains the key determinants of potency and the human CD4 moieties of D1D2-Igatp, this conjugate is expected to have the following unique set of HIV antiviral properties: (1) IC₉₀ infectivity neutralization values in the nanomolar range against HIV primary isolates; (2) lack of susceptibility to viable escape mutations, because the ligand is CD4, and because CD4-independence evolves concomitantly with constitutive exposure of neutralization-sensitive, highly conserved coreceptor binding site epitopes; (3) indefinite control of HIV viral replication, without the need for combination therapy, arising from properties (1) and (2); (4) improved HIV viral replication control when used in combination with other Highly Active Antiretroviral Therapy (HAART); (5) improved prevention of seroconversion when used in combination with other HAART shortly following known exposure to HIV. CRADA Opportunity: The Laboratory of Cell Biology of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Flexible, Polyvalent Antiviral Dendritic Conjugates for the Treatment of HIV/AIDS. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Targeting Poly-Gamma-Glutamic Acid to Treat Staphylococcus Epidermidis and Related Infections

Tue, 02 Oct 2007 02:00:00 GMT
Over the past decade, Staphylococcus epidermidis has become the most prevalent pathogen involved in nosocomial infections. Usually an innocuous commensal microorganism on human skin, this member of the coagulase-negative group of staphylococci can cause severe infection after penetration of the epidermal protective barriers of the human body. In the U.S. alone, S. epidermidis infections on in-dwelling medical devices, which represent the main type of infection with S. epidermidis, cost the public health system approximately $1 billion per year. Importantly, S. epidermidis is frequently resistant to common antibiotics.

Immunogenic compositions and methods for eliciting an immune response against S. epidermidis and other related staphylococci are claimed. The immunogenic compositions can include immunogenic conjugates of poly-gamma-glutamic acid (such as gammaDLPGA) polypeptides of S. epidermidis, or related staphylococci that express a gammaPGA polypeptide. The gammaPGA conjugates elicit an effective immune response against S. epidermidis, or other staphylococci, in subjects to which the conjugates are administered. A method of treating an infection caused by a Staphylococcus organism that expresses cap genes is also disclosed. The method can include selecting a subject who is at risk of or has been diagnosed with the infection by the Staphylococcus organism which expresses gammaPGA from the cap genes. Further, the expression of a gammaPGA polypeptide by the organism can then be altered. CRADA Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Human Bacterial Pathogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of poly-gamma-glutamic acid of staphylococci. Please contact Dr. Michael Otto at motto@niaid.nih.gov for more information.

Biomarkers for Tissue Status

Mon, 01 Oct 2007 06:00:00 GMT
Tissue regeneration and tumorigenesis are complex, adaptive processes controlled by cues from the host and from the tissue microenvironment. A variety of signals orchestrate the response to injury that results in regeneration and repair of a wound. Both tissue regeneration and carcinogenesis involve cell proliferation, survival, and migration that are controlled by growth factors and cytokines as well as inflammatory and angiogenic signals. Thus, wounds and cancers share a number of phenotypic similarities in cellular behavior, signaling molecules, and gene expression.

The inventors have compared global gene expression data from a model of renal regeneration and repair (RRR) with gene expression in renal cell carcinoma (RCC), and asked whether those two processes do, in fact, share molecular features and regulatory mechanisms. The majority (77%) of the genes expressed in RRR and RCC were concordantly regulated, whereas only 23% were discordant (i.e., changed in opposite directions). Thus, the genes regulated in the discordant direction provides diagnostic and therapeutic biomarkers to target RCC and not the normal regenerating tissue (kidney wound healing), as well as treating renal ischemia without promoting RCC. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Cancer Biology and Genetics, Wound Healing and Oncogenesis (NCI/CCR/LCBG), is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize topics of invention or related to cancer biology, metastasis, wound healing, bioinformatics, pharmacogenomics and therapeutic. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Cellular Receptor for Varicella-Zoster Virus, Methods of Inhibiting Spread of Varicella-Zoster and Methods of Increasing Stability and Infectivity of the Virus

Mon, 01 Oct 2007 10:00:00 GMT
This technology relates to identification of insulin degrading enzyme (IDE) as a cellular receptor for Varicella-Zoster-Virus (VZV), the etiologic agent of varicella (chickenpox) and zoster (shingles). Acute infection of VZV is followed by cell-associated viremia and the development of varicella rash. The virus establishes life-long latency in the nervous system and can reactivate to cause zoster. The mechanism of VZV entry into target cells and spread from cell-to-cell is not well understood. The inventors have shown that antibodies to IDE and soluble IDE partially inhibit infection with the virus in cell culture. Reducing the level of IDE in the cell (with siRNA), or blocking the ability of IDE to bind with a VZV glycoprotein, markedly diminishes cell-to-cell spread of the virus in cell culture and partially inhibits infection of cells with cell-free virus. This invention further describes molecules that may have a role in the treatment or prevention of VZV infections, including antibodies to IDE, peptides that block IDE-VZV interactions, and other molecules that block binding activity of IDE. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases, Medical Virology Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Jeffrey Cohen at jcohen@niaid.nih.gov for more information.

Multiple Donor Tissue-Derived Large IgM VH-Based F_ab Human Antibody Library

Mon, 01 Oct 2007 14:00:00 GMT
Available for licensing as a biological material for either internal use or commercial distribution is a human F_ab immunoglobulin/antibody fragment phage display library. The library contains 10¹⁰ F_abs derived from the peripheral blood of ten (10) healthy human donors. The high quality of the library was demonstrated in the successful selection of high affinity antibodies specific for Hendra and Nipah viruses; however, the library is useful for selecting a variety of antigen specific immunoglobulin/antibody F_ab fragments especially for cancer or viruses. Advantages and Benefits:
High affinity multi-purpose antibodies CRADA Opportunity: The NCI-Frederick is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutic, diagnostic or research reagent antibodies. Please contact Thomas Stackhouse at stackhot@mail.nih.gov or 301-846-5465 for more information.

An HIV Protein for Use as a Novel Therapeutic or Vaccine Component

Mon, 01 Oct 2007 18:00:00 GMT
Latent HIV presents a challenge for complete removal of the virus in infected individuals and is becoming an increasingly important consideration in the identification of potential HIV therapeutics or treatment regimens. These transcriptionally inactive HIV reservoirs lay dormant in a portion of infected cells and are capable of evading both host defenses and existing antiretroviral therapy. The present technology offers a potential solution for complete eradication of HIV in infected individuals.

This technology describes immunogenic and therapeutic compositions related to HIV p28TEV protein, the first protein expressed during HIV infection in the case of the pHXB2 isolate. p28TEV functions in the regulation of HIV transcription and may be important for the expression of latent virus. A number of p28TEV associated compositions are available for licensing and commercial development including: 1) the p28TEV polypeptide from one or more HIV clades, 2) nucleic acids encoding these p28TEV polypeptides, 3) a polypeptide with significant sequence homology to p28TEV, and 4) immunogenic fragments of these polypeptides. Additional compositions include antibodies and antagonists that act to inhibit p28TEV activity. Adjuvants, immunomodulators and compounds used in combination with p28 TEV for the treatment of HIV infection are also included in the available technology. CRADA Opportunity: The National Cancer Institute Vaccine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Methods of Targeting the Establishment of the HIV Viral Reservoir. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Retrovirus-Like Particles as Vaccines and Immunogens

Mon, 01 Oct 2007 22:00:00 GMT
This technology describes retrovirus-like particles and their production from retroviral constructs in which the gene encoding all but seven amino acids of the nucleocapsid (NC) protein was deleted. NC is critical for both genomic RNA packaging into the virion and viral integration into the host cell. Therefore, this deletion functionally eliminates two essential steps in retrovirus replication, thereby resulting in non-infectious retrovirus-like particles that maintain their full complement of antigenic proteins. Furthermore, efficient formation of these particles requires inhibition of the protease enzymatic activity, either by mutation to the protease gene in the construct or by protease inhibitor thereby ensuring the production of non-infectious retrovirus-like particles by altering two independent targets. These particles can be used in vaccines or immunogenic compositions. Specific examples using HIV-1 constructs are given. CRADA Opportunity: The NCI, CCR, AIDS Vaccine Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize whole retrovirus-like particle vaccines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Potent HIV-1 Entry Inhibitors and Immunogens

Tue, 02 Oct 2007 02:00:00 GMT
This technology relates to HIV antigenic constructs with flexible, heterologous linkers joining gp120 and gp41. The HIV-1 envelope Glycoprotein (Env) undergoes conformational changes while driving entry. The inventors developed these constructs to mimic some of the intermediate Env conformations. Tethered molecules of the invention were stable and potently inhibited cell fusion. Both gp120 and gp41 contain epitopes that may be necessary for the immune system to mount a robust and effective immune response to HIV. By connecting the two components, the current invention stabilizes the exposure of conserved epitopes, thereby increasing the chances that antibodies will form that react with these sites. CRADA Opportunity: The National Cancer Institute's Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop or evaluate immune response constructs. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Thiazepine Inhibitors of HIV-1 Integrase

Mon, 01 Oct 2007 06:00:00 GMT
The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). Drug-resistance is a critical factor contributing to the gradual loss of clinical benefit to treatments for HIV infection. Accordingly, combination therapies have further evolved to address the mutating resistance of HIV. However, there has been great concern regarding the apparent growing resistance of HIV strains to current therapies.

It has been found that a certain class of compounds including thiazepines and analogs and derivatives thereof are effective and selective anti-integrase inhibitors. These compounds have been found to inhibit both viral replication and the activity of purified HIV-1 integrase. The subject invention provides for such compounds and for methods of inhibiting HIV integras. CRADA Opportunity: The Laboratory of Molecular Pharmacology of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-integrase inhibitors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Optically Active Radio-labeled Reverse Transcriptase Inhibitors

Sat, 01 Sep 2007 10:00:00 GMT
Researchers at the NIH developed a novel and efficient method for preparing ¹⁸F-labeled reverse transcriptase inhibitors, particularly, ¹⁸F-labeled tenofovir analogues for use as PET imaging agents to monitor anti-retroviral drug biodistribution in anatomic compartments in HIV-1 infected patients. Fluorine-18 is often used to prepare radiotracers and radiopharmaceuticals, but its short half-life of 109 minutes demands efficient and rapid radiochemical syntheses and purification techniques. This technology provides high yields of labeled compounds utilizing rapid synthetic methods and HPLC purification in both racemic and optically active forms.

Available for licensing and commercial development are compositions of ¹⁸F-labeled tenofovir analogues, as well as methods of synthesis and methods of use for such labeled compounds. CRADA Opportunity: The NIBIB/IR/Positron Emission Tomography Radiochemistry Group and the NIAID Biostatistic Research Branch are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a Fluorine-18 radiolabeled analog of tenofovir. Please contact Peter Moy (NIBIB); 301/496-9270; moype@mail.nih.gov for more information.

Therapeutic HIV Vaccine and Associated Protocols

Sat, 01 Sep 2007 14:00:00 GMT
This technology describes a therapeutic HIV DNA vaccine to be administered to individuals who have previously experienced or are undergoing antiretroviral therapy (ART). The therapeutic DNA vaccine can also be administered in combination with a vector encoding an IL-15 and/or IL-15 receptor alpha (IL-15Ra) polypeptide. In primate studies, the technology was found to be particularly effective when the vaccine composition was administered by electroporation and expressed six (6) HIV antigens (including two (2) gag polypeptides and two (2) envelope polypeptides) and IL-15 and IL-15Ra. The antigens are typically modified with a destabilizing sequence, a secretory polypeptide and/or a degradation signal. Successive administration up to as many as nine resulted in continual boost of the immune response against the encoded antigen. A potent immunotherapeutic vaccine as described here could be an important technology for the fight against HIV/AIDS. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HIV DNA vaccines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Treatment of Primary Tumors and Tumor Metastases with TNF-alpha Antagonists

Sat, 01 Sep 2007 18:00:00 GMT
The role of TGF-beta1 in tumorigenesis is well-documented. However, the mechanism behind the induction of TGF-beta1 remains poorly understood. As a result, potential targets for the treatment of cancers associated with TGF-beta1 have escaped detection. This invention uncovers a two-step process of TGF-beta1 induction, thereby providing alternative targets for cancer treatment.

TGF-beta1 induction requires signaling through by IL-13 through IL13-Ralpha2. However, IL13-Ralpha2 must first be induced, requiring signaling by TNFalpha and IL4 or IL-13 through IL13-Ralpha1. Thus, by blocking TNFalpha signaling, one can block the expression of TGF-beta1. This invention concerns new methods of treating cancers associated with TGF-beta1 expression involving the administration of TNFalpha antagonists. CRADA Opportunity: The National Institutes of Health, NIAID, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize “Treatment of Primary Tumors and Tumor Metastases with TNF-alpha Antagonists.” Please contact Dr. Warren Strober at WStrober@niaid.nih.gov for more information.

A Transgenic Mouse Expressing Reverse Tetracycline-Controlled Transactivator in Melanocytes

Sat, 01 Sep 2007 22:00:00 GMT
Available for licensing are transgenic mice that allow for specific and inducible expression of proteins in melanocytes. Melanocytes are difficult to study because of their paucity in mammalian skin, and these mice present a readily available source of these cells and model to study melanocyte diseases such as melanoma of the skin and eye. The mice can be crossed with transgenic mice that harbor the green fluorescent protein (GFP) gene, resulting in melanocyte-specific GFP labeling. GFP labeling can aid in imaging and/or isolation of melanocytes via fluorescence activated cell sorting, and it can be used to study melanocytes at both the cellular and molecular level. CRADA Opportunity: The Laboratory of Cancer Biology and Genetics of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize use of transgenic mice that allow for specific and inducible expression of proteins in melanocytes. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Citrobacter freundii WR7011 as a Vaccine Strain or Source of Vi Capsular Antigen for Protection Against Typhoid Fever

Sun, 02 Sep 2007 02:00:00 GMT
According to the WHO, typhoid fever remains a serious public health problem throughout the world, with an estimated 16–33 million cases and 500,000 to 600,000 deaths annually. The Vi capsule of S. typhi, the causative agent of typhoid fever, is a surface-bound carbohydrate polymer to which antibodies have been shown to protect against typhoid fever. Purification of this polymer from virulent S. typhi strains poses a danger to those handling the live organisms. However, an unusual strain of Citrobacter freundii, WR7004, was mutated by the inventors to create a strain (WR7011) that makes Vi polysaccharide on its surface. Specifically, the strain was mutated using nitrosoguanidine. C. freundii WR7011 makes several times as much Vi polysaccharide as strains of S. typhi, is nonpathogenic, and is much safer to work with for Vi production or use as a vaccine strain. The inventors anticipate that this strain of C. freundii will reduce costs of purifying the Vi polysaccharide and also provide an increased level of safety during manufacture of the polysaccharide. CRADA Opportunity: The FDA-CBER Laboratory of Enteric and Sexually Transmitted Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Vi polysaccharide from Citrobacter freundii. Please contact Dr. Dennis J. Kopecko at 301-496-1893 or (dennis.kopecko@fda.hhs.gov) for more information.

Mutant Alleles of Hsp90 that Modulate the Lifespan of Yeast

Sat, 01 Sep 2007 06:00:00 GMT
Heat shock protein 90 (Hsp90) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses. They act as chaperones to other cellular proteins and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins.

This invention identifies Hsp90 mutant residues that affect the chronological lifespan of yeast. These mutations in addition to a deletion in the sch9 allele, the yeast homolog to human kinase AKT, can increase yeast lifespan from 45 to 57 days, approximately 20% longer than the wildtype strain. These genetically engineered yeast strains may have the longest chronological lifespan reported to date. CRADA Opportunity: The National Cancer Institute’s Urologic Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize models to study aging and longevity factors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods and Compositions for Treating FUS1 Related Disorders

Sat, 01 Sep 2007 10:00:00 GMT
The FUS1 gene residing in the 3p21.3 chromosome region may function as a tumor suppressor gene. In animal models, disruption of FUS1 is associated with an increased frequency of spontaneous vascular tumors and signs of autoimmune disease. The investigators have in vivo data that demonstrate that FUS1 null mutants show a consistent defect in NK cell maturation that correlate with changes in the expression of IL-15. Injection of IL-15 into FUS1 knockout mice completely rescued the NK cell maturation defect suggesting that FUS1 plays an important role in the development and activation of the mammalian immune system. CRADA Opportunity: The National Cancer Institute Basic Research Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cancer and immune disorder therapies Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Rapid Motion Perception MRI Navigator Method

Sat, 01 Sep 2007 14:00:00 GMT
Available for licensing and commercial development is a non-breathhold flow sensitive navigator technique for reducing respiratory motion artifacts in magnetic resonance (MR) images. The method, called Rapid Motion Perception (RaMP), tracks bulk translational motion of the heart in real-time. The position of the blood volume is a direct representation of the heart position. RaMP tracks fast-moving blood volume during systole as a marker for the heart position, while suppressing stationary or slow moving spins. This approach allows cardiac navigation in two orthogonal directions simultaneously, eliminates the need to obtain empirical correlations between the diaphragm and the heart, and increases tracking reliability among individual patients. The method uses a spoiled-Fast Low Angle Shot (FLASH) navigator and incorporates an alternating pair of bipolar velocity-encoding gradients. Data at 1.5T indicate that RaMP is capable of correcting bulk motion of the heart over multiple cardiac cycles to within +/-1.43 mm in the superior-inferior direction and +/- 0.84 mm in the anterior-posterior direction. CRADA Opportunity: The NHLBI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Lili Portilla at 301-594-4273 or via email at Lilip@nih.gov for more information.

Peptide Inhibitor of Cyclin Dependent Kinase 4 (CDK4) Derived from MyoD

Sat, 01 Sep 2007 18:00:00 GMT
This invention pertains to cell cycle regulation and the activity of the G1 cyclin-dependent kinase 4 (CDK4). The invention describes a 15 amino acid peptide and variants thereof derived from muscle determination factor, MyoD, which is an inhibitor of the CDK4. CDK4 is one of a number of cyclin-dependent kinases which control progression through the cell cycle through their ability to phosphorylate particular substrates at the correct phase of the cell cycle. CDK4 has been shown to be involved in cell cycle control through its ability to regulate the activity of the retinoblastoma protein, pRb, an activator of genes essential for cell division.

Inhibitors of the cyclin-dependent kinases, such as the peptides described in this invention, prevent cell cycle progression and induce cells to exit the cell cycle into the Go state. The peptides described in this invention prevent the phosphorylation of pRb by CDK4, an obligate step for entry into the cell cycle. Osteosarcomas and habdosarcomas are two types of tumors known to over-express pRb. The inhibitor described in this invention may be useful in treating these cancers or other diseases which have been specifically linked to over-expression of active pRb. CRADA Opportunity: The National Cancer Institute’s Laboratory of Biochemistry and Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the described cdk4 inhibitory peptides or equivalent peptide mimetics. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods for Prevention and Treatment of Polyomavirus Infection or Reactivation (E-179-2007)

Wed, 01 Aug 2007 22:00:00 GMT
Available for licensing and commercial development are methods of using Tranilast [N-(3',4'-dimethoxycinnamoyl)anthranilic acid] in the prevention and treatment of human polyomavirus infection. Treatment with Tranilast decreases viral protein expression for two human polyomavirus species, JC virus (JCV) and BK virus (BKV). Furthermore, the increase in JCV/BKV protein production observed upon the addition of TGF-beta could also be effectively abolished by Tranilast co-treatment. This is of relevance because TGF-beta has previously been demonstrated to increase during immunosuppressive conditions, including HIV infection and kidney transplantation.

JCV is responsible for demyelization of the central nervous system, which is observed in cases of progressive multifocal leukoencephalopathy (PML). PML is most frequently seen in patients with HIV/AIDS, but is also a contributing factor in fatalities in patients with leukemia, lymphoma, and connective tissue diseases, in addition to individuals receiving immunosuppressive therapy for autoimmune disorders or prevention of transplant rejection. BKV is associated with serious clinical syndromes such as viruria and viremia, ureteral ulceration and stenosis, and hemorrhagic cystitis and has a causative role in polyomavirus-associated nephrophathy in as many as 10% of all renal transplant recipients. Currently, there are no effective antiviral agents available to treat these opportunistic infections. In all observed cases, activation of either JCV or BKV in immunosuppressed patients has resulted in fatalities. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize treatment and prevention of polyomavirus infections in immunocompromised patients, with particular interest in JCV and demyelination. Please contact Melissa Maderia, Ph.D., at maderiam@mail.nih.gov for more information.

Probe Set Global Optimization

Thu, 02 Aug 2007 02:00:00 GMT
Available for licensing and commercial development are methods to optimize sequence-based assays such as microarrays, multiplexed PCR or multiplexed antibody methods. This computational method uses numerical optimization to identify an optimal probe set to be used in an assay for the measurement of a specified set of targets. The method incorporates the sequence information of the target (protein, DNA, RNA or other polymer), the assay characteristics, limits on probe set size and assay probe length in its optimization. The method selectively optimizes the total information provided by the assay within constraints of individual probe performance and coverage of all targets in the target set. For example, the target set of sequences could represent known viral or bacterial pathogens, or splice variants of a single gene. The method selectively identifies sequences within each target sequence with the best individual probe performance and providing the most information. An individual probe may be selected because it provides specific information about a single target (specificity) or because it increases (sensitivity) by providing replicate measurements of a sequence common to several targets.

The method’s software design allows for large (>10,000) target sets and large probe set sizes (2->1,000,000) While current selection criteria involve a time consuming iterative and manual process, the present invention allows for the identification of a quantitatively optimized probe set which balances probe performance criteria and simultaneously optimizes the sensitivity and specificity of the assay for a given set of targets. CRADA Opportunity: The National Heart, Lung and Blood Institute, Computational Biophysics Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, utilize or commercialize a method for optimizing sequence-based assays. Please contact Dr. Eric Billings, at (301) 496-6520 or via email at billings@helix.nih.gov for more information.

Recombinant Baculoviruses Containing Inserts of the Major Structural Genes (vp1) of the Human Polyomaviruses JCV and BKV

Wed, 01 Aug 2007 06:00:00 GMT
The development of sensitive and specific tests for JC virus and BK virus activity may provide tools essential in the steps required to find a treatment for these fatal infections. This invention describes a Recombinant Vpl protein (rVp1) that can be used 1) as an antigen source for ELISA assays 2) for studies of viral proteins in cells and 3) for the self assembly of icosahedral particles encapsidating DNA [gene expression of choice in range of up to 5.1kb size gene].

rVp1 can be utilized in ELISA assays to detect both JCV and BKV antibodies. The JCV and BKV rVp1 proteins may serve as antigens for the production of useful anti-sera and monoclonal-antibodies for polyomavirus research, as well as for the detection of existing and/or changing levels of antibodies in human sera by way of ELISA assays. Such ELISA studies allow for tracking of the spread and/or reactivation of polyomavirus infections in the human population, of special importance for individuals at high risk of polyomavirus associated pathologies. The rVp1s eliminate the need to produce infectious, native polyomavirus virions as antigens for such work.

The rVp1 proteins may also be utilized as vector delivery systems. The rVp1 proteins self-assemble into Virus-Like Particles (VLPs) which can be dissociated, reconstituted in the presence of exogenous DNA (that is non-specifically encapsidated), and then internalized through cell membranes that native virions normally cross. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize treatment and prevention of polyomavirus infections in immunocompromised patients. Please contact Melissa Maderia, Ph.D., at maderiam@mail.nih.gov for more information.

Design of Multi-functional RNA Nanoparticles and Nanotubes

Wed, 01 Aug 2007 10:00:00 GMT
The characteristic function of nanoparticles is their ability to deliver drug across biological barriers to the target site while protecting the drugs from the biological environment until they reach the target site. The present invention provides polyvalent RNA nanostructures comprising RNA I inverse (RNA Ii) or RNA II inverse (RNA IIi) like motifs that have multiple positions available for conjugation of therapeutic, diagnostic or delivery agents. The nanoparticles of the invention do not induce significant immune response by themselves and are smaller than currently available nanoparticles and therefore allow for increased efficiency of administration. The nanoparticles of this invention have the ability to deliver one or more different therapeutic agents in a single particle. Further, the RNA nanoparticles are also capable of self-assembly into nanotubes of various shapes which offer potentially broad uses in medical implants, gene therapy, nanocircuits, scaffolds and medical testing. CRADA Opportunity: The National Cancer Institute’s Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize RNA nanostructures. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Device and Method for Protecting Against Coronary Artery Compression During Transcatheter Mitral Valve Annuloplasty

Wed, 01 Aug 2007 14:00:00 GMT
Catheter-based mitral valve regurgitation treatments that use a coronary sinus trajectory or coronary sinus implant can have unwanted effects because the coronary sinus and its branches have been found to cross the outer diameter of major coronary arteries in a majority of humans. As a result, pressure applied by any prosthetic device in the coronary sinus (such as tension on the annuloplasty device) can compress the underlying coronary artery and induce myocardial ischemia or infarction.

Available for licensing and commercial development are devices and methods that avoid constricting coronary artery branches during coronary sinus-based annuloplasty. These devices and methods protect coronary artery branches from constriction during trans-sinus mitral annuloplasty. The device protects a coronary vessel from compression during mitral annuloplasty in which an annuloplasty element, such as a tensioning device, extends at least partially through the coronary sinus over a coronary artery. The device is a surgically sterile bridge configured for placement within the coronary sinus at a location where the coronary sinus passes over a coronary artery, so that the protection device provides a support for a mitral annuloplasty element, such as a compressive prosthesis, including a tension element when it is placed under tension. The protection device has an arch of sufficient rigidity and dimensions to support the tensioning element over the coronary artery, redistribute tension away from an underlying coronary artery, and inhibit application of pressure to the underlying artery, for example when an annuloplasty tension element is placed under tension during mitral annuloplasty.

In particular, the protective device can be a support interposed in the coronary sinus between the annuloplasty device and the coronary artery. The device may be substantially tubular so that the tensioning element is contained within the protective device and supported in spaced relationship to the coronary artery. An arch may be configured to extend between a proximal end and a distal end that are substantially collinear with one another so that the ends form stabilizing members such as feet that retain the bridge in position over the coronary artery.

The device may be used in methods of improving the function of a mitral valve in a subject in which an annuloplasty element, for example an element that exerts compressive remodeling forces on the mitral valve (such as a tensioning element), is introduced at least partially around the mitral valve, for example at least partially through the coronary sinus and over a coronary artery. The protective device is placed between the annuloplasty element and the coronary artery, with the annuloplasty element supported by the bridge of the device. Compressive remodeling forces are exerted by the annuloplasty device (for example by applying tension to alter the shape or configuration of the mitral valve annulus to reduce its circumference) while supporting the annuloplasty element on the bridge to inhibit application of pressure to the coronary artery. The function of the mitral valve in the patient is thereby improved without impairing coronary blood flow.

The annuloplasty element can be introduced at least partially around the mitral valve by advancing the annuloplasty element in an endovascular catheter through the vascular system to the heart and introducing the annuloplasty element and the protective device from the catheter into the coronary sinus through a coronary sinus ostium. In those embodiments in which the protective device includes an internal lumen, the annuloplasty element extends through the lumen of the protective device over the coronary artery so that the annuloplasty element is supported by the protective device. The protective device can be integrated directly into the annuloplasty element, such as a resilient or expandable device, or a tensioning element or tensioning material.

In other embodiments, this disclosure provides a method of improving function of a mitral valve in a subject who has mitral regurgitation by performing a mitral valve cerclage annuloplasty. In a particular disclosed example of the procedure, a guiding catheter is percutaneously inserted through the vasculature of a subject. The guiding catheter is introduced through the coronary sinus into the great cardiac vein, and a steerable microcatheter or other coaxial guiding catheter or steering device introduces a guidewire into a basal blood vessel such as the first septal coronary vein. From there the guidewire traverses under imaging guidance the septal myocardium or annulus fibrosis and reenters the right ventricle or right atrium. The guidewire is then retrieved using a vascular snare and the guiding catheter and guidewire are replaced with a tensioning system. The protective device is then introduced through the guiding catheter over or in tandem with the tensioning system so as to protect an underlying coronary artery when tension is introduced to perform the annuloplasty. CRADA Opportunity: The NHLBI Cardiovascular Branch is seeking statements of capability or interest from parties interested in collaborative research to further development, evaluate, or commercialize catheter-based cardiovascular devices. Please contact Peg Koelble, NHLBI Office of Technology Transfer and Development, at 301-594-4095 or koelblep@nhlbi.nih.gov.

Methods for Determining Hepatocellular Carcinoma Subtype and Detecting Hepatic Cancer Stem Cells

Wed, 01 Aug 2007 18:00:00 GMT
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, and it is very heterogeneous in terms of its clinical presentation as well as genomic and transcriptomic patterns. HCC can originate from both adult hepatocytes and hepatic progenitor cells. The extent of progenitor cell activation and the direction of differentiation are correlated with the severity of the disease. HCC patient variability indicates that HCC comprises several biologically distinct subtypes. This heterogeneity and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification.

Available for licensing are microRNA biomarkers that are associated with four HCC subtypes: hepatic stem cell-like, bile duct epithelium-like, hepatocytic progenitor-like, and mature hepatocyte-like. One unique profile is associated with HCC with features of liver stem cells and poor patient prognosis. It has both diagnostic and therapeutic value in the management of HCC patients. CRADA Opportunity: The National Cancer Institute, Laboratory of Human Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Immunogenic Peptides and Methods of Use for Treating Prostrate and Uterine Cancers

Wed, 01 Aug 2007 22:00:00 GMT
Cancer of the prostate is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men. Despite the use of standard therapy, including surgery, radiotherapy, chemotherapy, and/or hormonal therapy more than 30,000 men will die from prostate cancer. Moreover, current therapy has limited success against metastatic androgen insensitive prostate cancer. A potential treatment for prostate cancer is immunotherapy, either alone or in combination with standard therapies.

PAGE4 is an X chromosome-linked cancer-testis antigen that is highly expressed in prostate and uterine cancers. To this end, Drs. Jeffery Schlom, Kwong Tsang, and Ira Pastan have identified and characterized novel PAGE4 cytotoxic T-cell lymphocyte (CTL) epitopes and enhanced agonist epitopes. Preclinical studies performed by Dr. Schlom and colleagues indicate that the PAGE4 agonist epitopes bind HLA-A2 molecules at lower peptide concentrations, form more stable peptide HLA-A2 complexes, induce higher levels of production of INF-gamma, Granzyme B, TNF-alpha, IL-2, and lymphotactin by PAGE4 specific T-cell lines, and T-cell lines generated against the agonist peptide were more efficient at lysing human tumor cells expressing native PAGE4. Thus, these agonist epitopes of PAGE4 could be incorporated into immunotherapy protocols, and may constitute an alternative and/or additional approach for the treatment of PAGE4 expressing prostate and uterine cancers. CRADA Opportunity: The Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Cross-protective Influenza Vaccine That Protects Against Lethal H5N1 Challenge

Thu, 02 Aug 2007 02:00:00 GMT
Concerns about a potential influenza pandemic and its prevention are a regular part of health news, with bird (avian) influenza (prominently including H5N1 strains) being a major concern. Vaccination is one of the most effective ways to minimize suffering and death from influenza. Currently, there is not an effective way to vaccinate against avian influenza without knowing what subtype and strain will circulate. The technology described here relates to use of influenza A matrix 2 (M2) protein of a sequence derived from one subtype to induce immunity protective against infection with other subtypes, an approach made possible by the fact that M2 is highly conserved among different influenza strains. The M2 component can be expressed from a DNA vaccine or recombinant viral vector, can be a protein or peptide, or can involve immunizing with one form and boosting with another, for example a DNA or viral vector followed by or preceded by a polypeptide. The M2 component can be used either alone or in combination with other influenza components, and can be administered with or without adjuvant. Specifically, mouse studies showed that the DNA vaccine priming followed by recombinant adenoviral boosting with constructs expressing M2 from an H1N1 strain protected against a lethal challenge with an H5N1 strain. Such cross-protection would be beneficial in a seasonal or pandemic influenza vaccine product. The current approach offers several advantages over traditional influenza vaccine approaches, including a) ease and speed of production without need for eggs, b) vaccine manufacture not based upon surveillance to determine dominant strain(s), and c) effectiveness despite antigenic shift for the components HA and NA of circulating viruses. CRADA Opportunity: The Center for Biologics Evaluation and Research, Office of Cellular, Tissue, and Gene Therapies, Division of Cellular and Gene Therapies, Gene Therapy and Immunogenicity Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize matrix 2 (M2) vaccines protective against influenza A subtypes, including high-pathogenicity avian strains, differing from the strain from which the vaccine was derived. Please contact Dr. Suzanne Epstein at 301-827-0450 or suzanne.epstein@fda.hhs.gov for more information.

Isolation, Cloning and Characterization of New Adeno-Associated Virus (AAV) Serotypes

Wed, 01 Aug 2007 06:00:00 GMT
Adeno-associated viruses (AAV) are used in gene delivery, but with limited success due to toxicity. The novel AAVs described in this technology may be more effective and useful in gene therapy applications.

This invention relates to new adeno-associated viruses (AAV), vectors and particles derived therefrom and also provides methods for delivering specific nucleic acids to cells using the AAV vectors and particles. The inventors cloned and sequenced the genomes of AAVs found in twelve (12) simian adenovirus isolates and determined that the AAVs were novel. Ten (10) of these isolates had high similarity to AAV1 and AAV6 (>98%). Despite the high homology to AAV6, these novel AAVs demonstrated distinct cell tropisms and reactivity towards a panel of lectins, suggesting that they may use a distinct entry pathway. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Gene Therapy and Therapeutics Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adeno-associated viruses. Please contact David W. Bradley, Ph.D. at bradleyda@nidcr.nih.gov for more information.

Specific Binding Agents for KSHV vIL-6 that Neutralize a Biological Activity

Wed, 01 Aug 2007 10:00:00 GMT
Kaposi’s sarcoma-associated herpes virus (KSHV) is an oncogenic herpes virus originally identified in AIDS associated Kaposi’s sarcoma (KS) lesions, the most common tumor associated with HIV infection. KSHV encodes various proteins that have characteristics associated with cellular growth and transformation, including viral (v) IL-6 (KSHV vIL-6). These viral proteins display structural homology to their cellular counterparts, and human and vIL-6 are multifunctional cytokines that have been shown to induce vascular endothelial growth factor and other factors.

Available for licensing are binding agents that neutralize vIL-6 biological activities, methods of diagnosing and treating KSHV disorders, and methods to monitor KSHV patient response to treatment. Deregulation of cellular IL-6 expression is known to contribute to tumor development, suggesting that KSHV-derived vIL-6 could be part of a viral strategy to promote malignant transformation. Neutralizing activity of anti-vIL-6 antibodies may provide a potential therapeutic for KSHV disorders such as HIV, Castleman’s disease, and primary effusion lymphoma. CRADA Opportunity: The National Cancer Institute’s Laboratory of Cellular Oncology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutics for Kaposi’s sarcoma-associated herpes virus (KSHV). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Dysphagia Rehabilitation (Swallowing Recovery): Vibro-Tactile Stimulation Device and Method for Motor Control Recovery

Sun, 01 Jul 2007 14:00:00 GMT
Available for licensing and/or commercial development under a scientific collaboration, are device and method patents for volitional swallowing with a substitute sensory system. The inventions are potentially applicable to a wide variety of indications, including recovery post-stroke and post ex-tubation for example, after coronary bypass surgery. The device is being tested in dysphagic patients in two, on-going clinical trials at the National Institutes of Health. A collaborator or licensee is needed to support further clinical trials, validation studies, and final package development.

Device:
For the device patent, upon activation a vibrator moves and vibrates the larynx. Patients can initiate sensory stimulation immediately prior to the patient's own initiation of a swallow. Specifically, the device allows the patient coordinate muscular movement with a button press to permit volitional swallowing. The device can also include a movement sensor for monitoring pressure on the patient's larynx and a swallowing detector. The swallowing detector includes a piezoelectric stretch receptor and a stimulator, coupled to the movement sensor, for applying pressure to a patient's larynx prior to swallowing. The device can also be used to automatically trigger and retrain swallowing to prevent aspiration pneumonia post stroke or post extubation.

Method:
For the method patent, the instant device has also been claimed in a patent application asserting rights for improving voluntary initiation of swallowing in neurologically impaired patients. Swallowing recovery alleviates the risk of aspiration by augmenting volitional control using a simultaneous motor act (e.g., such as pressing a button to indicate when they are ready to swallow). It is believed that such motor training also initiates sensory stimulation, immediately preceding the motor act, and that such sensory stimulation enhances excitation of a central pattern generator in the brain stem that augments the volitional control of swallowing. This principle is applicable to other neurological impairments; their associated enhancement of voluntary motor act control by the patient initiating immediately concurrent and related sensory stimulations. Neurological impairments that are contemplated include reflex actions involving interactions between afferent and efferent paths (at the spinal cord or in the brain stem) as well as higher order interactions. This invention includes methods for treating neurologically impaired humans using devices such as those that produce vibratory stimulation, pressure stimulation, auditory stimulation, temperature stimulation, visual stimulation, olfactory stimulation, taste stimulation, or a combination of these. Combinations of two or more stimulation types are particularly useful. For example, the combined use of button press training with simultaneous vibratory and pressure stimulation on the neck to augment feedback to the brain stem swallowing centers to facilitate voluntary control of swallowing (thought to be largely an involuntary brain stem function) is particularly useful for treating dysphagic patients. Alternatively automatic cycles of stimulation at intervals during the day can be used for intensive retraining of swallowing post stroke or post-extubation to prevent aspiration. CRADA Opportunity: For research and development collaborations with inventors, contact Heather Gunas at 301-435-3944 or email at gunash@mail.nih.gov.

Rational HIV Therapeutic Design

Sun, 01 Jul 2007 18:00:00 GMT
This technology describes the structural nature of a highly conserved tyrosine-sulfate binding pocket on the HIV-1 gp120 envelope glycoprotein and the use of this information to design HIV-entry inhibitors that target it. The binding pocket was characterized by structural determinations of the N-terminus of CCR5 with gp120 as well as of the complex of 412d (a tyrosine-sulfated antibody) with gp120 and CD4. The N terminus of CCR5, like the 412d antibody, is tyrosine-sulfated. In spite of structural differences between these molecules, gp120 recognizes both tyrosine-sulfated molecules in similar ways, indicating that this specificity can be exploited in the design of HIV-entry inhibitors. CRADA Opportunity: The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases as well as the Laboratory of Bioorganic Chemistry of the National Institute of Diabetes and Digestive and Kidney Diseases are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tyrosine-sulfated CCR5-based inhibitors of HIV-1 infection. Please contact Susan Ano for more information.

Treatment of Cocaine-Induced Fetal Brain Injury

Sun, 01 Jul 2007 22:00:00 GMT
This invention is helpful in diagnosing and treating fetal brain injury caused by cocaine exposure. It is estimated that one percent of pregnant women use cocaine at some point in their pregnancies. In addition to increased risk for complications during pregnancy such as stillbirth, stroke, and low birth weight, cocaine appears to affect both short-term and long-term mental development. Animal studies indicate changes in brain development and behavior in response to prenatal cocaine exposure, and research has shown that children exposed to cocaine before birth are at risk of learning and behavioral problems. Children exposed to cocaine before birth are twice as likely to have significant delays in mental skills by age two. Treatment for pregnant women who use cocaine is typically directed to cocaine avoidance, but these treatments do not directly address the problem of cocaine-induced damage in the developing fetus, particularly in the fetal brain. Thus, there exists a critical need for drugs that can prevent or treat cocaine-induced damage to the fetal brain.

The inventors have demonstrated that N-oxidative metabolism of cocaine causes oxidative stress to the endoplasmic reticulum, which ultimately results in cell cycle arrest and abnormal development of the fetal cerebral cortex. They have also shown that cytochrome P450 inhibitors can block the inhibition of cell proliferation by cocaine. This invention discloses methods of using cytochrome P450 inhibitors to treat or prevent cocaine-induced fetal brain injury, as well as methods for screening for inhibitory drugs to treat or prevent cocaine-induced fetal brain injury. CRADA Opportunity: The Cellular Neurobiology Research Branch of the National Institute on Drug Abuse is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the development of P450 inhibitors and related compounds for the prevention of cocaine-induced developmental brain damage Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method of Treating or Preventing Oxidative Stress-related Diseases (stroke and neurodegenerative diseases, wound healing and cardiovascular diseases)

Mon, 02 Jul 2007 02:00:00 GMT
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produce oxidative stress to DNA, lipids and proteins thus causing cellular and tissue damage. A number of diseases are associated with oxidative stress including Alzheimer's disease, ischemic stroke, heart disease, cancer, hepatitis, and autoimmune disease. Uric acid is a natural antioxidant effective in reducing ROS and research has shown that uric acid contributes approximately two-thirds of all free radical scavenging capacity in plasma. Because uric oxide is too insoluble to be used as a therapeutic agent, scientists at the NIH developed uric acid analogs with improved anti-oxidative and solubility properties for use as free radical scavengers or antioxidants. These analogs increased survival of PC12 and hippocampal neurons after challenge by Fe, MPP and Glutamate. When administered to a mouse model of focal ischemic stroke, these compounds protect neuronal cells from ROS and reduce brain damage and ameliorate neurological deficits. Other studies show a single application of these analogs on skin lacerations in mice decreased the time for wound repair. Available for licensing are methods of treating ischemic stroke and wound healing, and for the prevention or treatment of other oxidative stress-related diseases, such as epilepsy, Parkinson's disease and dementia. CRADA Opportunity: The National Institute on Aging, Laboratory of Neurosciences is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the described uric acid analogue technology in the treatment of neurodegenerative diseases, wound healing and cardiovascular disease. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Mice Genetically Deficient in the Chemoattractant Receptor FPR (formyl peptide receptor)

Sun, 01 Jul 2007 06:00:00 GMT
The present research tool is a knockout mouse model (FPR^-/-) that lacks the high affinity N-formylpeptide receptor (FPR), created by targeted gene disruption.

N-formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N-formylpeptide receptor signaling in vivo may be important in antibacterial host defense, although direct proof has been lacking. The inventors have found that FPR^-/- mice have no obvious developmental defects and do not develop spontaneous infection when derived in specific pathogen-free conditions. This suggests that, under these conditions, FPR is dispensable. However, when challenged with L. monocytogenes, FPR-deficient mice have accelerated mortality and increased bacterial burden in liver and spleen early after infection, which suggests a role for FPR in host defense, specifically through regulation of innate immunity. CRADA Opportunity: The Laboratory of Molecular Immunology, NIAID, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize FPR knockout mice. Please contact Philip Murphy, M.D. at Tel: 301-496-8616 and/or pmm@nih.gov for more information.

Methods for Expression and Purification of Immunotoxins

Sun, 01 Jul 2007 10:00:00 GMT
The invention concerns immunotoxins and methods of making the immunotoxins. Targeting of the immunotoxins occurs via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. As a result, the immunotoxin can be used to treat autoimmune disease, malignant T cell-related cancers, and graft-versus-host disease. The toxin portion of the immunotoxin is engineered to maintain bioactivity when produced in yeast, specifically Pichia pastoris. This system allows the production of dimeric antibody fragments with increased binding affinity and potency. CRADA Opportunity: The National Institute of Mental Health, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of expression and purification of immunotoxins. Please contact David Neville at davidn@mail.nih.gov for more information.

Cyclic Phosphopeptide Inhibitors of Protein Phosphatase 2C Delta, Wip1

Sun, 01 Jul 2007 14:00:00 GMT
This technology involves the development of specific peptides that can be used as anti-cancer agents, particularly as promoters of apoptosis. The inventors have modified the natural substrate of the Wip1 protein phosphatase in order to produce the inhibitors, allowing for specific and efficient inhibition of Wip1. These peptides represent the first Wip1 peptide inhibitors. The inhibitors can be combined with other pro-apoptosis therapeutics to improve patient survival, providing an advantage to previous pro-apoptosis approaches.

Wip1 (PP2Cdelta or PPM1D) is a protein phosphatase that negatively regulates cell- cycle arrest and apoptosis by preventing p53-mediated cell-cycle arrest and apoptosis. Wip1 is overexpressed in several human cancers, including breast cancer, ovarian clear cell adenocarcinoma and neuroblastoma, suggesting it may play an important role in oncogenesis. Inhibiting Wip1 may be a necessary step for inducing apopotsis and prohibiting tumor growth, accentuating the need for Wip1-directed therapies. Because these peptide inhibitors are the first specific Wip1 inhibitors, they represent the first opportunity to pursue this therapeutic strategy. CRADA Opportunity: The National Cancer Institute Center for Cancer Research, Laboratory for Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Cyclic Phosphopeptide Inhibitors of Protein Phosphatase 2C Delta, Wip1. Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.

Dual Expression DNA Influenza Vaccine

Sun, 01 Jul 2007 18:00:00 GMT
The NIH is pleased to announce a single vector DNA vaccine against influenza as available for licensing. The single vector expresses both hemagglutinin (HA) and matrix (M) proteins, generating both humoral and cellular immune responses. The vaccine candidate completely protected mice against homologous virus challenge and significantly improved survival against heterologous virus challenge. A robust and reliable vaccine supply is widely recognized as critical for seasonal or pandemic influenza preparedness. The advantages offered by this vaccine make it an excellent candidate for further development. CRADA Opportunity: The CBER/FDA Division of Viral Products is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the HA/M single vector DNA vaccine. Please contact Zhiping Ye at 301-435-5197 or zhiping.ye@fda.hhs.gov for more information.

Potential Serum Bio-Markers for Alpha-fetoprotein (AFP) Negative Hepatocellular Carcinoma

Sun, 01 Jul 2007 22:00:00 GMT
This technology relates to improved methods of detecting hepatocellular carcinoma (HCC) by using new biomarkers. The overexpression of Gpc3, Mdk, SerpinI1, PEG-10 and QP-C correlates with the presence of HCC, even in small tumors. By comparing the expression levels of at least three of these markers in subject samples with their expression levels in control samples, the presence of HCC can be diagnosed. The method can also be used to monitor the progression, and regression of HCC.

HCC is a common and aggressive cancer with a high mortality rate. The high mortality rate stems from an inability to diagnose the cancer at an early stage in patients, due to the lack of available biomarkers for HCC. Currently, HCC is diagnosed by measuring the levels of serum alpha-fetoprotein (AFP); however, AFP is not always present in HCC tumors, especially small tumors. CRADA Opportunity: The National Cancer Institute, Laboratory of Human Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize new biomarkers for hepatocellular carcinoma (HCC). Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Methods and Materials for Identifying Polymorphic Variants, Diagnosing Susceptibilities, and Treating Disease

Mon, 02 Jul 2007 02:00:00 GMT
This invention relates to materials and methods associated with polymorphic variants in two enzymes involved in folate-dependent and one-carbon metabolic pathways important in pregnancy-related complications and neural tube birth defects: MTHFD1 (5,10-methylenetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthase) and methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L). These enzymes are extremely important in the promotion of DNA synthesis, a process that is critical for normal placental and fetal development.

Recently, the inventors have discovered that a MTHFD1 polymorphism is also a maternal genetic risk factor for placental abruption, premature separation of a normally implanted placenta. This polymorphism may also be a risk factor for first and second trimester miscarriages. Diagnostic and therapeutic methods are provided in this invention involving the correlation of polymorphic variants in MTHFD1 and MTHFD1L and other genes with relative susceptibility for various pregnancy-related and other complications such as cancer, cardiovascular disease, developmental anomalies and psychiatric illnesses. Both nutrient status and genetic background are independent yet interacting risk factors for impaired folate metabolism. However, the mechanisms that lead to pathology or the mechanisms whereby folate prevents these disorders are unknown. Therefore, a diagnostic and therapeutic invention of this kind would significantly improve the detection and treatment of disorders associated with folate metabolism. CRADA Opportunity: The National Human Genome Research Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Claire Driscoll at 301-402-2537 or cdriscol@mail.nih.gov for more information.

A Gene Therapy to Treat Lung Cancer

Sun, 01 Jul 2007 06:00:00 GMT
This invention relates to the identification of a new tumor suppressor gene named Caliban from Drosophila melanogaster and Serologically determined colon cancer antigen gene 1 (Sdccag1) from humans. Sdccag1 is inactive in human lung cancer cells but active in normal lung cells. When full length Caliban or Sdccag1 is expressed in human lung cancer cells they lose their tumorigenicity. This suggests that Caliban/Sdccag1 could be used as both a therapeutic and diagnostic for cancer. CRADA Opportunity: The National Institute of Child Health and Human Development is seeking statements of capability or interest from parties interested in collaborative research to obtain pre-clinical data to be used to further develop, evaluate, or commercialize Caliban/Sdccag1 as a novel therapeutic and diagnostic target for cancer and other diseases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Peptide Mimotope Candidates for Otitis Media Vaccine

Sun, 01 Jul 2007 10:00:00 GMT
This technology describes peptide mimotopes of lipooligosaccharides (LOS) from nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis that are suitable for developing novel vaccines against the respective pathogens, for which there are currently no licensed vaccines. The mimotopes not only immunologically mimic LOSs from NTHi and M. catarrhalis but will also bind to antibodies specific for the respective LOS. NTHi and M. catarrhalis are common pathogens that cause otitis media in children and lower respiratory tract infections in adults. The effectiveness of a vaccine could be increased by substitution of a LOS epitope with a peptide mimic. Preliminary experiments have shown that some of the mimic peptides conjugated to a carrier were as effective as their respective LOS-based vaccine in stimulating a humoral immune response in rabbits. A single consensus amino acid sequence was identified for M. catarrhalis, while four such sequences were identified for NTHi. Thus, the identified peptides are promising candidates for developing novel vaccines for NTHi or M. catarrhalis. CRADA Opportunity: The NIDCD Vaccine Research Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Peptide vaccines derived from LOS of NTHi or M. catarrhalis. Please contact Marianne Lynch, a technology development specialist, at 301-594-4094 or lynchm2@mail.nih.gov for more information.

Methods of Inducing Immune Tolerance Using Immunotoxins

Fri, 01 Jun 2007 14:00:00 GMT
The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of rejection response in a patient, including graft-versus-host disease and transplantation of organs, tissues and cells into a host. In a specific embodiment of the invention, the transplant involves pancreatic islet cells. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of resting T cells, resulting in an accentuation of immune tolerizing responses and an increased tolerance to transplants and grafts. The toxin portion of the immunotoxin is genetically engineered to maintain bioactivity when recombinantly produced in Pichia pastoris. Data are available in transgenic animals expressing human CD3epsilon which supports the effects of the immunotoxin against T cells. CRADA Opportunity: The National Institute of Mental Health, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of using the immunotoxins for the treatment of rejection response in a patient. Please contact David Neville at davidn@mail.nih.gov for more information.

A Novel Treatment for Non-Small Cell Lung Cancer Using Mesothelin-Targeted Immunotoxins

Fri, 01 Jun 2007 18:00:00 GMT
Mesothelin is a glycoprotein, whose expression has been largely restricted to mesothelial cells in normal tissues, although epithelial cells of the trachea, tonsil, fallopian tube, and kidney have shown immunoreactivity. Mesothelin has been shown to be expressed in several cancers including pancreatic carcinomas, gastric carcinomas and ovarian carcinomas, and has the potential of being used as a tumor marker and a novel target for the development of new treatments.

The technology relates to the finding that some non-small cell lung cancers (NSCLC) express the antigen mesothelin. Targeting the tumors with antibodies or immunotoxins that specifically bind mesothelin can be a potential new treatment for non-small cell lung cancer. The SSIP immunotoxin and its variants that specifically bind to mesothelin can be used for the treatment of NSCLC. CRADA Opportunity: The National Cancer Institute's Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-mesothelin antibodies and immunotoxins. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Novel Discriminatory Small Peptide Inhibitor of Hsp90 Targeting Oncogenic Kinases

Fri, 01 Jun 2007 22:00:00 GMT
Heat shock protein 90 (Hsp90) is a molecular chaperone required for stability and function for many proteins (clients). Presently, there are clinical trials focusing on small molecule Hsp90 inhibitors; however, pharmacologic Hsp90 inhibition causes destabilization, ubiquitination and proteasome-degradation of all client proteins indiscriminately.

Hsp90 was found to be overexpressed in tumor cells; thereby making Hsp90 a promising molecular target for cancer therapy. Additionally, some Hsp90-dependent client proteins (non-kinases) were identified as putative tumor suppressors, suggesting that indiscriminate degradation of all Hsp90 client proteins is not ideal. Finding a molecular inhibitor that discriminately inhibits Hsp90 that would target only client kinase proteins would be an ideal therapeutic agent for cancer treatment.

The current invention is a short peptide that inhibits Hsp90 that prevents the recognition and function of client kinase proteins, and promotes the degradation of client kinase proteins, while not affecting other non-kinase client proteins. CRADA Opportunity: The NCI Urologic Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize peptide inhibitor of Hsp90. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Total Emission Detection System for Multi-Photon Microscopy

Sat, 02 Jun 2007 02:00:00 GMT
Available for licensing and commercial development is a novel two-photon microscope system, which would allow improved fluorescent light collection, the use of less excitation power and deeper penetration of tissue and isolated cells. Multi-photon fluorescence microscopy (MPFM) is an imaging technique that can investigate biological processes to sub-cellular resolution at depths of hundreds of microns below the surface of biological tissues. MPFM provides higher resolution imaging of tissues than confocal imaging, but is currently limited by the use of inefficient light collection systems, which lead to detection of only a fraction of the light that is emitted from the sample. The new system consists of an array of mirrors, lenses, and reflecting surfaces designed to collectively maximize the probability of collecting all emitted fluorescent light to a detector, thereby providing enhanced brightness of light detected from the sample and an increase in signal-to-noise ratio (SNR). This increase is SNR can be used to improve time resolution, reduce laser power requirements and reduce photodynamic damage. CRADA Opportunity: The NHLBI Light Microscopy Core Facility is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a total emission detection system for multi-photon imaging. Please contact Alan Deutch, Ph.D., Director of the NHLBI Office of Technology Transfer and Development, at 301-402-5579 or via Email at deutcha@nhlbi.nih.gov for more information.

Immunotoxin with in-vivo T cell Suppressant Activity

Fri, 01 Jun 2007 06:00:00 GMT
The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of autoimmune diseases and T cell malignancies. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. The toxin portion of the immunotoxin is genetically engineered to maintain bioactivity when recombinantly produced in Pichia pastoris. Data are available in transgenic animals expressing human CD3epsilon which supports the effects of the immunotoxin against T cells. CRADA Opportunity: The National Institute of Mental Health, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of using the immunotoxins for the treatment of autoimmune diseases and T cell malignancies. Please contact David Neville at davidn@mail.nih.gov for more information.

Synthetic Macrolides Inhibit Breast Cancer Migration

Fri, 01 Jun 2007 10:00:00 GMT
This technology relates to the synthesis of several novel macrocylic compounds (macrolides), built upon a quinic acid-containing scaffold, which are potent inhibitors of tumor cell migration. Specifically, the new molecules have been shown to inhibit breast cancer cell migration in vitro.

Tumor metastasis or cell migration is a multi-step process in which primary tumor cells spread or migrate by invading adjacent tissues and/or metastasizing to distance sites. Thus, one approach to cancer treatment may be the inhibition of tumor migration. The initial observation that migrastatin, a macrolide natural product first isolated from a Streptomycete, inhibits tumor cell migration gave rise to the synthesis of the analogs with increased potency and tumor cell selectivity reported here. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, is seeking parties interested in collaborative research to develop larger scale syntheses of the most potent macrolides and/or analogs thereof, and the conduct toxicology and other efficacy studies related to these macrolides. Please contact Dr. Carole Bewley at caroleb@mail.nih.gov or Rochelle S. Blaustein at Rochelle.Blaustein@nih.gov for more information.

Methods for Prevention and Treatment of Polyomavirus Infection or Reactivation

Fri, 01 Jun 2007 14:00:00 GMT
Available for licensing and commercial development are methods of using two MAP kinase kinase (MEK) inhibitors, PD98059 and U0126, in the prevention and treatment of polyomavirus infection. Decrease in viral protein expression upon treatment with the MEK inhibitors has been demonstrated for two polyomavirus species, JC virus (JCV) and BK virus (BKV). It is believed that these MEK inhibitors may also be effective against other polyomavirus species in which TGF-beta expression is elevated.

JCV is responsible for the demyelination of the central nervous system which is observed in cases of progressive multifocal leukoencephalopathy (PML). PML is most frequently seen in patients with HIV/AIDS, but is also a contributing factor in fatalities in patients with leukemia, lymphoma, and connective tissue diseases, in addition to individuals receiving immunosuppressive therapy for autoimmune disorders or prevention of transplant rejection.

BKV is associated with deadly clinical syndromes such as viruria and viremia, utreteral ulceration and stenosis, and hemorrhagic cystitis. BKV also causes polyomavirus-associated nephrophathy in 1-10% of all renal transplant recipients.

Currently, no effective antiviral agents are available to treat these opportunistic infections. In all observed cases, activation of either JCV and BKV in immunosuppressed patients has resulted in fatality. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize treatment and prevention of polyomavirus infections in immunocompromised patients. Please contact Melissa Maderia, Ph.D. at maderiam@mail.nih.gov for more information.

DLC-1 Gene Deleted in Cancers

Fri, 01 Jun 2007 18:00:00 GMT
Chromosomal regions that are frequently deleted in cancer cells are thought to be the loci of tumor suppressor genes, which restrict cell proliferation. Recurrent deletions on the short arm of human chromosome 8 in liver, breast, lung and prostate cancers have raised the possibility of the presence of tumor suppressor genes in this location.

The inventors have discovered the deletion of human DLC-1 gene in hepatocellular cancer (HCC) cells. They have performed in vitro experiments demonstrating the deletion in over 40% of human primary HCC and in 90% of HCC cell lines. The DLC-1 gene is located on human chromosome 8p21.3-22, a region frequently deleted in many types of human cancer. DLC-1 mRNA is expressed in all normal tissues tested, but it has either no or low expression in a high percentage of several types of human cancer, such as liver, breast, lung, prostate cancers. Through in vitro and in vivo tumor suppression experiments, the inventors further demonstrated that DLC-1 acts as a new tumor suppressor gene for different types of human cancer. CRADA Opportunity: The National Cancer Institute, Laboratory of Experimental Carcinogenesis, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostics based on tumor suppressor genes. Please contact John D. Hewes, Ph.D., at 301/435-3121 or hewesj@mail.nih.gov for more information.

A Gene Expression Signature Identifying Pro-Angiogenic Genes in Ovarian Tumor Endothelial Cell Isolates

Fri, 01 Jun 2007 22:00:00 GMT
Cancer is a heterogeneous disease that requires multimodality therapy. Most of the therapeutic approaches for ovarian cancer have focused on chemotherapy, which primarily targets proliferating tumor cells. Women with ovarian cancer are typically asymptomatic and they are often diagnosed at an advanced stage and have poor survival. Despite an 80% positive patient response rate to surgery and chemotherapy, most patients will experience tumor recurrence within two years. A majority of women who die of ovarian cancer will have ovarian epithelial carcinomas.

The inventors have discovered a unique proangiogenic biomarkers isolated from ovarian endothelial cells. By targeting tumor angiogenesis by inhibiting endothelial cells that support tumor growth, this technology provides methods to diagnose and ovarian cancer in its early stages. CRADA Opportunity: The National Cancer Institute’s Cell and Cancer Biology Branch, Molecular Mechanisms Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D., at 301/435-3121 or hewesj@mail.nih.gov for more information.

A MicroRNA Profile for Androgen Responsive Prostate Cancer

Sat, 02 Jun 2007 02:00:00 GMT
This invention describes a microRNA gene expression profile in prostate cancers that correlates with androgen responsiveness. Most prostate cancers are androgen sensitive and can be treated with anti-androgen therapies. Tumors non-responsive to anti-androgen therapy are more aggressive and needs alternative therapeutic interventions. Additionally, the microRNAs discovered can also be potential targets for developing new prostate cancer drugs. CRADA Opportunity: The NCI/SAIC-Frederick, Advanced Technology Program, Laboratory for Molecular Technology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize microRNA diagnostic markers in cancer. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Diagnostic and Therapeutic Use of Brother of the Regulator of Imprinted Sites (BORIS) Alternative Splice Forms

Fri, 01 Jun 2007 06:00:00 GMT
This technology identifies twenty five (25) new alternatively spliced transcripts of the BORIS gene. The transcripts lead to the expression of seventeen different protein isoforms with variable N- and C-termini encoded by BORIS gene locus. Differential expression levels of BORIS isoforms were observed in different cancers. While some BORIS alternative splice variants were expressed at different levels in all types of cancers, other expressed forms are specific to particular cancer(s). CRADA Opportunity: The NIAID Laboratory of Immunopathology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods of cancer diagnostics and treatment based on detection of BORIS isoforms. Please contact Cecilia Pazman at pazmance@niaid.nih.gov or (301) 451-3526 for more information.

Retrovirus Packaging Cell Lines Based on Gibbon Ape Leukemia Virus

Fri, 01 Jun 2007 10:00:00 GMT
Gene therapy and gene transfer have recently been recognized as effective therapeutic tools to combat diseases. Accordingly, market demands for vectors and carriers to facilitate such interventions have surged in recent years. Retroviral vectors provide an efficient and safe means of gene transfer to eukaryotic cells. The present invention relates to genetic engineering involving retrovirus packaging cells that produce retroviral vectors. Specifically, the invention involves the expression plasmids encoding the envelop glycoproteins of a family of primate type C retrovirus, namely, the Gibbon Ape leukemia virus (GALV). Recombinant vectors derived from murine leukemia virus (MLV) have been widely used to introduce genes in human gene therapy clinical trials. A key determinant for their use in clinical gene therapy is the availability of packaging cell lines capable of producing large amounts of virus with identical titers. The present invention describes the packaging cell lines that produce MLV-based gene transfer vectors with the envelope from gibbon ape leukemia virus. Retroviral vectors produced are of high titer and have an expanded host range providing a means for gene transfer to a wide range of animal species. The gene transfer vectors produced are non-infectious and there was no evidence of production of helper virus, making these vectors safe. These cell lines are critical for producing large amounts of standardized vector necessary for efficient for in vivo and ex vivo gene transfer. Therefore, this invention has a significant commercial application as a tool in the development of diagnostic and therapeutic interventions related to gene transfer and gene therapy. CRADA Opportunity: The National Institute of Mental Health, Laboratory of Cellular and Molecular Regulation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the Gibbon Ape leukemia virus (GALV) packaging cell line. Please contact Suzanne Winfield at winfiels@mail.nih.gov for more information.

Development of a Novel High Throughput Assay to Measure Cell-Infection with Vaccinia Strains Expressing Reporter Genes

Fri, 01 Jun 2007 14:00:00 GMT
Critical to developing a vaccine against viral infections is an assay to measure the neutralizing antibody present in blood of vaccine recipients. The currently available tests are labor intensive and require 5-6 days to complete. The inventors have designed a high throughput vaccinia neutralization assay, which offers several advantages over the assays that are currently used. It is completed in as little as 24 hours, it is sensitive, highly reproducible, requires only 50 µl of plasma and uses automated readout. This assay is based on the use of recombinant vaccinia virus (vSC56) expressing a bacterial gene coding for the enzyme b-galactosidase (b-Gal) under the control of a synthetic early/late promotor. Another recombinant virus expressing an inducible reporter gene (Luciferase) is also being tested in neutralization assay. These assays may be of value in the clinical trials of new smallpox vaccines, for evaluations of new vaccinia immunoglobulin (VIG) and anti-viral agents under development. The technology itself may be adapted for construction of neutralization assays for other viruses and intracellular pathogens. CRADA Opportunity: The CBER/FDA Laboratory of Retrovirus Research is seeking statements of capability or interest from parties interested in collaborative research to further develop or evaluate novel anti-vaccinia agents including monoclonal antibodies and vaccines. Please contact Hana Golding at Tel: 301-827-0784 or E-mail: hana.golding@fda.hhs.gov for more information.

Endotracheal Tube Using Unique Leak Hole to Lower Dead Space

Fri, 01 Jun 2007 18:00:00 GMT
Through injury or diseases, human or animal lungs may become too weak to sustain a sufficient flow of oxygen to the body and to remove adequate amounts of expired carbon dioxide. The present invention is a tracheal tube ventilation apparatus which efficiently rids patients of expired gases and promotes healthier breathing. This is accomplished by creating one or more leak holes in the wall of the endotracheal tube above the larynx, such as in the back of the mouth (i.e., oropharynx), so that expired gases can leak out of the endotracheal tube. The described apparatus is a two stage tube where the first stage has a smaller diameter such that it fits within the confined area of the lower trachea and the second stage has a larger diameter, which fits properly within the larger diameter of the patient's pharynx. The endotracheal tube is preferably wire reinforced and ultra-thin walled so as to reduce airway resistance. The invention substantially reduces endotracheal dead space and is expected to benefit those patients with both early and late stage acute respiratory failure, and reduce or obviate the need for mechanical pulmonary ventilation in many patients.

CRADA Opportunity: The NHLBI/Pulmonary Critical Care Medicine Branch (PCCMB) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize innovative endotracheal tube technology. Please contact Marianne Lynch at 301-594-4094 or lynchm@nhlbi.nih.gov for more information.

CC Chemokine Receptor 5 DNA, New Animal Models and Therapeutic Agents for HIV Infection

Fri, 01 Jun 2007 22:00:00 GMT
Chemokine receptors are expressed by many cells, including lymphoid cells, and function to mediate cell trafficking and localization. CC chemokine receptor 5 (CCR5) is a seven-transmembrane, G protein-coupled receptor (GPCR) which regulates trafficking and effector functions of memory/effector T-lymphocytes, macrophages, and immature dendritic cells. Chemokine binding to CCR5 leads to cellular activation through pertussis toxin-sensitive heterotrimeric G proteins as well as G protein-independent signalling pathways. Like many other GPCRs, CCR5 is regulated by agonist-dependent processes which involve G protein coupled receptor kinase (GRK)-dependent phosphorylation, beta-arrestin-mediated desensitization and internalization.

Human CCR5 also functions as the main coreceptor for the fusion and entry of many strains of human immunodeficiency virus (HIV-1, HIV-2). HIV-1 transmission almost invariably involves such CCR5-specific variants (designated R5); individuals lacking functional CCR5 (by virtue of homozygosity for a defective CCR5 allele) are almost completely resistant to HIV-1 infection. Specific blocking of CCR5 (e.g. with chemokine ligands, anti-CCR5 antibodies, CCR5-blocking low MW inhibitors, etc.) inhibits entry/infection of target cells by R5 HIV strains. Cells expressing CCR5 and CD4 are useful for screening for agents that inhibit HIV by binding to CCR5. Such agents represent potential new approaches to block HIV transmission and to treat infected people. A small animal expressing both human CCR5 along with human CD4 supports entry of HIV into target cells, a necessary hurdle that must be overcome for development of a small animal model (e.g. transgenic mouse, rat, rabbit, mink) to study HIV infection and its inhibition.

The invention embodies the CCR5 genetic sequence, cell lines and transgenic animals, the cells of which coexpress human CD4 and CCR5, and which may represent valuable tools for the study of HIV infection and for screening anti-HIV agents. The invention also embodies anti-CCR5 agents that block HIV env-mediated membrane fusion associated with HIV entry into human CD4-positive target cells or between HIV-infected cells and uninfected human CD4-positive target cells. CRADA Opportunity: The NIAID Laboratory of Molecular Immunology and Laboratory of Viral Diseases are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize CCR5-related products. Please contact Philip Murphy (301-496-8616, pmm@nih.gov) or Edward Berger (301-402-2481, edward_berger@nih.gov) for more information.

Vibrio cholerae O139 Conjugate Vaccines

Sat, 02 Jun 2007 02:00:00 GMT
Cholera remains an important public health problem. Epidemic cholera is caused by two Vibrio cholerae serotypes O1 and O139. The disease is spread through contaminated water. According to information reported to the World Health Organization in 1999, nearly 8,500 people died and another 223,000 were sickened with cholera worldwide. This invention is a polysaccharide-protein conjugate vaccine to prevent and treat infection by Vibrio cholerae O139 comprising the capsular polysaccharide (CPS) of V. cholerae O139 conjugated through a dicarboxylic acid dihydrazide linker to a mutant diphtheria toxin carrier. In addition to the conjugation methods, also claimed in the invention are methods of immunization against V. cholerae O139 using the conjugates of the invention. The inventors have shown that the conjugates of the invention elicited in mice high levels of serum antibodies to CPS, a surface antigen of Vibrio cholerae O139, that have vibriocidal activity. Clinical trials of the two most immunogenic conjugates have been planned by the inventors. The conjugate vaccine is aimed for long lasting immunity, especially in young children, and can be administered in concurrent with routine vaccines. CRADA Opportunity: The NICHD/LDMI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Vibrio cholera O139 or O1 conjugate vaccines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Enhanced T-cell Activation by Costimulation: An Effective Immunotherapy for Cancer and Infectious Diseases

Tue, 01 May 2007 06:00:00 GMT
Cancer immunotherapy is a recent approach where tumor associated antigens (TAAs), which are primarily expressed in human tumor cells and not expressed or minimally expressed in normal tissues, are employed to generate a tumor specific immune response. Specifically, these antigens serve as targets for the host immune system and elicit responses that result in tumor destruction. The initiation of an effective T-cell immune response to antigens requires two signals. The first one is antigen specific via the peptide/major histocompatibility complex and the second or "costimulatory" signal is required for cytokine production, proliferation, and other aspects of T-cell activation.

The present technology describes recombinant poxvirus vectors encoding at least three or more costimulatory molecules and TAAs. The use of three costimulatory molecules such as B7.1, ICAM-1 and LFA-3 (TRICOM®) has been shown to act in synergy with several tumor antigens and antigen epitopes to activate T cells. The effects with TRICOM® were significantly greater than with one or two costimulatory molecules. Laboratory results support the greater effect of TRICOM® to activate both CD4+ and CD8+ T cells. The invention also describes the use of at least one target antigen or immunological epitope as an immunogen or vaccine in conjunction with TRICOM®. The antigens include but are not limited to carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), and MUC-1.

The combination of CEA, MUC-1, and TRICOM® is referred to as PANVAC® and the combination of PSA and TRICOM® is referred to as PROSTVAC®. CRADA Opportunity: A CRADA partner for the further co-development of this technology is currently being sought by the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI.

The CRADA partner will:

Generate and characterize recombinant poxviruses expressing specific tumor-associated antigens, cytokines, and/or T-cell costimulatory factors,

Analyze the recombinant poxviruses containing these genes with respect to appropriate expression of the encoded gene product(s),

Supply adequate amounts of recombinant virus stocks for preclinical testing,

Manufacture and test selected recombinant viruses for use in human clinical trials,

Submit Drug Master Files detailing the development, manufacture, and testing of live recombinant vaccines to support the NCI-sponsored INDs,

Supply adequate amounts of clinical grade recombinant poxvirus vaccines for clinical trials conducted at the NCI Center for Cancer Research (CCR), and

Provide adequate amounts of vaccines for extramural clinical trials through a clinical agreement with the Division of Cancer Treatment and Diagnosis, NCI.

NCI will:

Provide genes of tumor-associated antigens, cytokines and other immunostimulatory molecules for incorporation into poxvirus vectors,

Evaluate recombinant vectors in preclinical models alone and in combination therapies,

Conduct clinical trials of recombinant vaccines alone and in combination therapies, and

Provide Drug Master Files currently supporting the clinical use of the recombinant poxvirus vaccines.

If interested in the above-described CRADA, please submit a statement of interest and capability to Kevin Brand, J.D. in the NCI Technology Transfer Center at kb229t@nih.gov or 301-451-4566.

Humanized Anti-Carcinoma CC49 Monoclonal Antibodies

Tue, 01 May 2007 10:00:00 GMT
The technology describes the humanization of a murine anti-carcinoma antibody CC49 which has been shown to react with Tumor Associated Glycoprotein 72 (TAG-72), an antigen which is expressed on human breast, ovarian, colorectal, and other carcinomas.

The invention includes a new method of humanization of a rodent antibody which is based on grafting all the Complementarity Determining Residues (CDRs) of a rodent antibody onto a human antibody framework. Additionally, the method identifies Specificity Determining Residues (SDRs), the amino acid residues in the hypervariable regions of an antibody that are most critical for antigen binding activity and of rendering any antibody minimally immunogenic in humans by transferring the SDRs of the antibody to a human antibody framework. The resulting humanized antibodies, including CDR variants thereof (including a CH2 deleted version), are also embodied in the invention, as are methods of using the antibodies for therapeutic and diagnostic purposes.

Furthermore, these antibodies are suitable for radiolabeling for the application in radioimmunotherapy (RIT) based treatment of several cancers. Phase I results of radioimmunotherapy for ovarian cancer using ⁹⁰Yttrium-CC49 murine monoclonal antibodies have shown promising results and confirms feasibility of the use of these antibodies for RIT. Promising pharmacokinetic data for the radiolabeled humanized antibodies in colon carcinoma xenograft models were recently published. CRADA Opportunity: The National Cancer Institute's Laboratory of Tumor Immunology and Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-carcinoma antibodies. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Inhibitors of Ubiquitin E1

Tue, 01 May 2007 14:00:00 GMT
The present invention discloses novel pyrazolidinyl compounds that inhibit undesired cell proliferation. The compounds inhibit ubiquitin E1 and can be useful for regulating protein ubiquitination. Specifically, the novel pyrazolidinyl compounds can stabilize p53 and induce apoptosis in mammalian cells through selective inhibition of ubiquitin E1.

Ubiquitin-mediated proteolysis is an important pathway of non-lysosomal protein degradation that controls the timed destruction of a number of cellular regulatory proteins including p53. The ubiquitin pathway leads to the covalent attachment of poly-ubiquitin chains to target substrates which are then degraded by a multi-catalytic proteosome complex.

The compounds can be useful in the treatment of solid and disseminated cancers or other undesired cell proliferation disease or retroviral infections such as HIV. CRADA Opportunity: The National Cancer Institute’s Laboratory of Protein Dynamics and Signaling is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of ubiquitin E1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Peptide Inhibitors of Fibronectin and Related Collagen-Binding Proteins

Tue, 01 May 2007 18:00:00 GMT
Fibronectin has been implicated in a variety of cell contact processes, including cell attachment and migration. Fibronectin interacts with collagen through its gelatin-binding domain and this interaction is fundamental to the organization of extracellular matrices and the behavior of these cells on substrates. Fibronectin is essential for the attachment and migration of many cells, including various tumor and cancer cells.

The issued patents disclose peptide compositions having binding affinity for fibronectin, as well as methods for binding fibronectin with a fibronectin-binding peptide and methods for inhibiting fibronectin-mediated cell adhesion. The peptides disclosed are derived from the extracellular matrix protein thrombospondin, which is a modular adhesive glycoprotein that binds to the gelatin binding domain of fibronectin. These peptides are strong inhibitors of fibronectin-mediated cell adhesion. As such, they may be applicable to a variety of indications including cancer, wound healing, and connective tissue diseases. CRADA Opportunity: The National Cancer Institute, Laboratory of Pathology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these peptides. Please contact John D. Hewes, Ph.D. at (301) 435-3121 or hewesj@mail.nih.gov for more information.

Diagnosing and Treating Cancer Using beta-Catenin Splice Variants

Tue, 01 May 2007 22:00:00 GMT
This application discloses and claims inventions which may be used alone or together. One group of inventions relates to early detection diagnostic, prognostic and patient monitoring methods (“Diagnostic Methods”). The other group of inventions relates to methods of treatment. Both groups of inventions have particular application with respect to esophageal squamous cell cancers (ESCC) or other types of adenocarcinomas and squamous cell carcinomas.

The Diagnostic Methods are useful in evaluating the status of preneoplastic lesions as well as tumor tissue. Because of this, the methods can be used to track the progression or regression of disease in many types of cell samples from normal to dysplasia to cancer.

The Diagnostic Methods involve measuring the level of one or more pairs of transcripts or the protein products of these pairs of transcripts or the cellular localization of the transcripts or proteins. The primary transcripts or protein products useful in this method are those of the beta-Catenin gene (CTNNB1). In particular, the levels of the 16A and 16B CTNNB1 transcripts or protein products are of importance in carrying out the methods of this patent application. Other gene transcripts or protein products that may be used in conjunction with CTNNB1 16A and 16B to provide additional information are WAF1 (p21) and cMYC.

The treatment methods include employing small interfering RNA molecules (siRNAs) as a means to alter the expression of one or more of these particular CTNNB1 transcripts. More specifically, preferred siRNA molecules can be used to alter the expression of the CTNNB1 transcripts 16A and/or 16B. These siRNA molecules may be single-stranded (ss) or double-stranded (ds) and may be delivered using a construct capable of producing the siRNA molecule upon delivery to the target cell. CRADA Opportunity: The National Cancer Institute, Division of Cancer Epidemiology and Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a method of diagnosing and treating cancer using beta-Catenin splice variants. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Self-Assembling Nanoparticles Composed of Transmembrane Peptides and Their Application for Specific Intra-Tumor Delivery of Anti-Cancer Drugs

Wed, 02 May 2007 02:00:00 GMT
The current invention discloses peptide based nanoparticles as an alternative to liposomes. The nanoparticles have a diameter of 8-10 nm and are much smaller than a liposome thus providing better tumor penetration. Peptides corresponding to transmembrane domains of a number of integral membrane proteins have been discovered that spontaneously self-assemble in aqueous solutions into stable and remarkably uniform nanoparticles. The nanoparticles of the current invention are fully synthetic, and their surfaces can be functionalized with ligands that provide specific binding to cell surface receptors overexpressed on tumor cells. Thus, they are even more specific for tumor targeting.

Nanoparticles constructed from transmembrane domains of certain receptors and transporters have biological activity of their own and inhibit metastasis or drug resistance thus sensitizing tumors to therapy. Hydrophobic drugs can be easily entrapped inside the nanoparticles, which not only solve the problem of drug insolubility under physiological conditions, but also generate a form of a drug that concentrates in tumors due to enhanced permeability and retention (EPR) effects. CRADA Opportunity: The NCI Center for Cancer Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize self-assembling nanoparticles with intrinsic anti-tumor activity. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

New High-Throughput and Bioinformatic Tools to Identify and Use Genomic DNA Sequence Dimorphisms (Indels)

Tue, 01 May 2007 06:00:00 GMT
This invention describes new methods to identify genomic DNA sequence dimorphisms called indels and to determine their biological consequences. "Indels" refers to large insertions and deletions, a form of variation in DNA sequences, that can cause genotypic and phenotypic differences between cells, tissues, individuals, populations or species. The technology describes new bioinformatic tools and high-throughput methods to identify such dimorphisms. Additionally, the technology provides new assays to distinguish genomic sequences by genotyping, understand the role of such indels in altering gene expression, for example in disease pathogenesis, develop new models for variation in genomes and in gene expression, and improve methods for the molecular diagnosis and treatment of disease. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Mouse Cancer Genetics Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize identification and use of such genomic DNA sequence insertion/deletion dimorphisms (indels). Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.

Inhibition of ABC Transporters by Transmembrane Domain Analogs

Tue, 01 May 2007 10:00:00 GMT
ABC transporters contain multiple transmembrane domains and are involved in the translocation of a variety of substrates across cell membranes. Upregulation of these transporters contributes to multiple drug resistance in cancer chemotherapy wherein these transporters export chemotherapeutic agents out of cancer cells. The inventors have found that P-glycoprotein and ABCG2 transporter can be effectively inhibited by properly modified peptides corresponding to certain transmembrane domains. This inhibition can be used to overcome drug resistance in resistant tumors. CRADA Opportunity: The National Cancer Institute's Structural Biophysics Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of multiple drug resistance proteins. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

STAMP, A Novel Cofactor and Possible Steroid Sparing Agent, Modulates Steroid-induced Induction or Repression of Steroid Receptors

Tue, 01 May 2007 14:00:00 GMT
Steroid hormones such as androgens, glucocorticoids, and estrogens are used in the treatments of many diseases. They act to regulate many physiological responses by binding to steroid receptors. However, because steroid receptors are expressed in many tissues, efforts to therapeutically modify the effects of steroid hormones on a specific tissue or on a specific receptor of the steroid receptor family often cause undesirable effects in other tissues or on other receptors. STAMP (SRC-1 and TIF-2 Associated Modulatory Protein), a novel protein that acts to lower the concentration of steroid hormone needed to induce (or repress) selected target genes by regulating steroid receptor synthesis, offers an novel approach for reducing the severity of unwanted side-effects, thereby increasing the ability to use steroid hormone therapies. CRADA Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Steroid Hormones Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize STAMP, a steroid cofactor. Please contact Dr. Stoney Simons at steroids@helix.nih.gov for more information.

TMC1, a Deafness-Related Gene

Tue, 01 May 2007 18:00:00 GMT
Hearing loss is a common communication disorder affecting nearly 1 in 1,000 children in the United States alone, and nearly 50% of adults by the age of eighty. Hearing loss can be caused by environmental and disease-related factors; however, hearing loss due to genetic factors accounts for approximately 50% of cases.

The NIH announces the isolation of two novel genes involved in hearing; TMC1, short for transmembrane channel-like gene 1. The inventors have discovered that dominant and recessive mutations in TMC1 underlie two forms of hereditary deafness, known as DFNA36 and DFNB7/11. TMC1 encodes a protein required for normal function of the mammalian hair cell, which plays a critical role within the hearing pathway that detects sound in the inner ear.

The invention discloses TMC1 nucleic acids, vectors, and cells. Also disclosed are methods of detecting hearing loss, or a predisposition to hearing loss, due to a mutation in TMC1, as well as methods for identifying agents that interact with the TMC1 gene in a cell. Nucleic acids and methods of use for TMC2, a gene closely related to TMC1, are also disclosed. CRADA Opportunity: The NIDCD Otolaryngology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology as well as collaborate on further pre-clinical and clinical studies with the TMC2 gene mutations. Please contact Ms. Marianne Lynch at 301-402-5579 or via email at lynchm@nhlbi.nih.gov for more information.

Vaccine Against Eschericha coli 0157 Infection, Composed of Detoxified LPS Conjugated to Proteins

Tue, 01 May 2007 22:00:00 GMT
This invention is a conjugate vaccine to prevent infection by E. coli 0157:H7, particularly in young children under 5 years of age. E. coli 0157:H7 is an emerging human pathogen which causes a spectrum of illnesses with high morbidity and mortality, ranging from diarrhea to hemorrhagic colitis and hemolytic-uremic syndrome (HUS). Infection with E. coli 0157:H7 occurs as a result of consumption of water, vegetables, fruits or meat contaminated by feces from infected animals, such as cattle. The most recent large outbreak in the U.S. was from contaminated bag spinach. The conjugate is composed of the O-specific polysaccharide isolated from E. coli 0157, or other Shiga-toxin producing bacteria, conjugated to carrier proteins, such as non-toxic P. aeruginosa exotoxin A or Shiga toxin 1. A Phase I clinical trial, involving adult humans, showed the vaccine is safe and highly immunogenic. Adults, after one injection containing 25 µg of antigen, responded with high titers of bactericidal antibodies. Similarly in a phase II study, fifty 2-to-5- years old children in US were injected with the conjugate vaccines. There were only mild local adverse reactions. More than 90% children responded with greater than 10 fold rise of E. coli O157 antibodies of bactericidal ability. Thus the conjugates of the invention are promising vaccines, especially for children and the elderly, who are most likely to suffer serious consequences from infection. CRADA Opportunity: The National Institute of Child Health and Human Development, Laboratory of Developmental and Molecular Immunity, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Vaccine for E. coli O157 for Children and Adults. Please contact John Hewes, Ph.D., at 301-496-0477 or hewesj@mail.nih.gov for more information.

A Neuronal Avalanche Size (NAS) Assay to Screen for Cognitive Enhancers and Anti-Epileptics

Mon, 02 Apr 2007 02:00:00 GMT
Currently available methods of detecting and measuring EEG activity only crudely classify normal and abnormal activity or distinguish epileptic activity early in the onset of its deviation from normal activity. Available for licensing are methods for recognizing a new pattern of EEG activity called neuronal avalanche size (NAS) that has been correlated with cognitive function and epilepsy. The NAS uses extracellular field potentials to measure the distribution of synchronized neurons in the cortex (neuronal avalanches) and thus the state of the cortical network. When the avalanche size reaches a power law with a slope of -3/2, the system is in the critical state and the cortical network is functioning optimally to spread information throughout the network. If the system slope deviates from -3/2, the system is outside the critical state and is either epileptic or sub-critical. In animal studies measurement of NAS quantified a drug’s potential to increase cognitive functioning and induce or reduce epilepsy.

The NAS assay may thus enable high-throughput in vitro screens to select anti-epileptics and cognitive enhancing drugs for continued drug development. Because avalanches represent scale-invariant dynamics they can also be recorded using surface (EEG) electrodes. This technology may thus be useful in assessing cognitive function, epileptic pathology and in selecting and monitoring drug therapy for epileptic patients. CRADA Opportunity: The NIMH/Section of Neural Network physiology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the NAS assay. Please contact Dietmar Plenz at plenzd@mail.nih.gov for more information.

Antibodies Against TL1A, a TNF-Family Cytokine, for the Treatment and Diagnosis of Autoimmune Inflammatory Diseases

Sun, 01 Apr 2007 06:00:00 GMT
Autoimmune inflammatory diseases occur in greater than five percent of the United States population; this disease group includes asthma, multiple sclerosis, rheumatoid arthritis, and lupus. Treatments generally include immunosuppressants or anti-inflammatory drugs, which can have serious side effects; recently, more specific immunomodulatory therapies such as TNF-alpha antagonists have been developed.

In experiments with mice, NIAMS inventors have shown that the interaction between the TNF family ligand TL1A with its receptor, DR3, is critical for development of disease in asthma, inflammatory bowel disease and multiple sclerosis. They have also developed anti-TL1A antibodies that prevent disease in mouse models of rheumatoid arthritis and inflammatory bowel disease.

This technology describes anti-mouse TL1A and anti-human TL1A monoclonal antibodies that may be useful for the development of diagnostics and therapeutics for autoimmune inflammatory disease, as well as methods of treating such disease by blocking the interaction between TL1A and DR3. CRADA Opportunity: The National Institute of Arthritis and Musculoskeletal and Skin Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the anti-mouse TL1A and anti-human TL1A monoclonal antibodies. For collaboration opportunities, please contact Cecilia Pazman at pazmance@mail.nih.gov.

GDF15, a Marker and Cause of Morbidity in Thalassemia

Sun, 01 Apr 2007 10:00:00 GMT
The invention includes methods for the measurement of Growth Differentiation Factor 15 (GDF15, also known as MIC-1 or NAG-1) levels in order to diagnose or predict disease severity in patients with thalassemia and with related complications, as well as methods for treating thalassemia by administration of a GDF15 antagonist. Also disclosed is a method to reduce hepcidin levels by administration of GDF15, a GDF15 substitute, or GDF15 agonist.

GDF15 is a member of the TGF-Beta superfamily of proteins, which are known to control cell proliferation, differentiation, and apoptosis in numerous cell types. The inventors are additionally interested in investigating the role of GDF15 in other disorders characterized by ineffective erythropoiesis, as well as the role of GDF15 in the regulation of iron metabolism.

Thalassemia consists of a group of inherited diseases of the red blood cells, arising from deficient or absent production of globin chains. In beta-thalassemia, also known as Cooley's anemia or Mediterranean anemia, defective globin production reduces the number and viability of red blood cells, causing anemia and subsequent expansion of bone marrow. As a result of marrow expansion distorted bone formation ensues. Beta thalassemia, the most severe form of thalassemia, also results in iron overload, which is the major cause of beta-thalassemia mortality worldwide. As a result of iron overload, the patient may develop hypropituitarism, hypothyroidism, hypoparathyrodism, diabetes, arthropathy, cirrhosis and cardiopulmonary disease. Treatment of beta-thalassemia involves frequent blood transfusions and chelation therapy to remove excess iron from the blood.

In thalassemia, the patient's hepcidin expression is pathologically suppressed. Hepcidin is a protein synthesized in the liver, which reduces iron absorption in the body. The inventors have identified GDF-15 as a hepcidin-suppressing cytokine that is overexpressed in thalassemia. GDF15 levels in blood plasma have been found to be dramatically elevated in beta-thalassemia patients compared to healthy donors and patients with hereditary hemochromatosis, another form of iron overload disease. CRADA Opportunity: The NIDDK's Molecular Medicine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the role of GDF-15 in other disorders characterized by ineffective erythropoiesis, as well as the role of GDF15 in the regulation of iron metabolism. Please contact Dr. Jeffery L. Miller at Jeff.Miller1@nih.hhs.gov or 301/402-2373 for more information.

Preparation of (R,R)-Fenoterol and (R,R)-or (R,S)-Fenoterol Analogues and Their Use in Treating Congestive Heart Failure

Sun, 01 Apr 2007 14:00:00 GMT
This technology is directed to the discovery of (R,R)- and (R,S,)-fenoterol analogues which are highly effective and selective at binding beta2-adrenergic receptors. The patent application includes methods of using such compounds and compositions for the treatment of cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease. CRADA Opportunity: The National Institute on Aging, Laboratory of Clinical Investigation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of fenoterol analogues in the treatment of cardiac disorders. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Novel DNA Vaccine for the Treatment of Malignancies Expressing Immature Laminin Receptor Protein

Sun, 01 Apr 2007 18:00:00 GMT
This invention describes a new potent chemoattractant-based DNA vaccine to evoke therapeutic anti-tumor responses against tumors. The vaccine targets the antigen presenting cells (APCs) to efficiently present an antigen to MHC class I and class II molecules to induce tumor specific CD4 and CD8 T cell responses.

The antigen tested is a highly conserved oncofetal antigen named immature laminin receptor protein (OFA-iLRP) that is preferentially expressed in malignant tissues. The vaccine construct consists of novel fusion proteins with enhanced binding affinities to augment antigen processing and antitumor responses. CRADA Opportunity: The National Institute on Aging, Immunotherapeutics Unit, Laboratory of Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize simple and potent vaccines that target embryonic antigens expressed in tumors. Please contact John D. Hewes, Ph.D. at (301) 435-3121 or hewesj@mail.nih.gov for more information.

New Mouse T Cell Receptors as Potential Therapeutic Agents for the Treatment of Metastatic Cancer

Sun, 01 Apr 2007 22:00:00 GMT
Adoptive immunotherapy is one of the most promising new therapeutic approaches to treat cancer.

T cell receptors (TCR) are the proteins responsible for the T cell's ability to recognize infected or transformed cells. A TCR consists of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit the recognition signal by interacting with other proteins.

This invention describes the identification of two mouse TCRs that target a common and highly expressed melanoma antigen, gp100, expressed by human cancers. These TCRs, have superior (100-1000 times) biological function compared to other human tumor-specific TCR that are currently in use in experimental trials using genetically engineered T cells. Therefore, these new TCRs represent potential therapeutic agents that can be used in the treatment of metastatic cancers, especially melanomas. CRADA Opportunity: The Surgery Branch, NCI, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this T cell receptor that is specific for human tumors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method for Promoting Stem Cell Proliferation and Survival

Mon, 02 Apr 2007 02:00:00 GMT
This technology describes a method to promote stem cell survival and proliferation by manipulating the phosphorylation state of Stat3 protein. This method has been shown to enhance survival and proliferation in stem cell cultures in vitro, and also in neuronal precursor cells in vivo. The methods include use of a Notch ligand and growth factors such as FGF-2 or insulin to promote neural stem cell survival and proliferation. The technology is also directed to a population of stem cells expressing STAT3 phosphorylated at serine 727. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke, Laboratory of Molecular Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents that inhibit or induce phosphorylation of STAT3 protein and survival of stem cells and precursor cells. Please contact Martha Lubet at 301/435-3120 or lubetm@mail.nih.gov.

Identification of Anti-HIV Compounds Inhibiting Virus Assembly and Binding of Nucleocapsid Protein to Nucleic Acid

Sun, 01 Apr 2007 06:00:00 GMT
The subject invention identified two groups of active anti-viral compounds. The first group comprises aromatic, antimony-containing compounds, while the second group comprises aromatic tricarboxylic acid. Both groups were shown to inhibit viral particle assembly and inhibit the binding of nucleocapsid protein to nucleic acid. Recently, the first group also demonstrated the capability of blocking HIV-1 viral entry into CD4+ cells through binding to CD4 and inhibiting gp120-CD4 interaction, and they are well tolerated in vivo. Hence, these compounds are potent inhibitors of HIV and act via a novel mechanism, ideal for developing a new generation of anti-HIV medicine. CRADA Opportunity: The NCI HIV DRP Retroviral Replication Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these active anti-viral compounds. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Major Neutralization Site of Hepatitis E Virus and Use of this Neutralization Site in Methods of Vaccination

Sun, 01 Apr 2007 10:00:00 GMT
Hepatitis E is endemic in many countries throughout the developing world, in particular on the continents of Africa and Asia. The disease generally affects young adults and has a very high mortality rate, up to 20%, in pregnant women. This invention relates to the identification of a neutralization site of hepatitis E virus (HEV) and neutralizing antibodies that react with it. The neutralization site is located on a polypeptide from the ORF2 gene (capsid gene) of HEV. This neutralization site was identified using a panel of chimpanzee monoclonal antibodies that are virtually identical to human antibodies. Since this neutralization site is conserved among genetically divergent strains of HEV, the neutralizing monoclonal antibodies may be useful in the diagnosis, treatment and/or prevention of hepatitis E. Furthermore, immunogens that encompass this neutralization site may be used in vaccination to effectively prevent, and/or reduce the incidence of HEV infection. Polypeptides containing this neutralization site may be useful in evaluating vaccine candidates for the production of neutralizing antibodies to HEV. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these antibodies or structures they interact with. For more information, please contact Robert H. Purcell, M.D., Co-chief, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 50 South Drive, Bldg. 50, Rm. 6523, Bethesda, MD 20892-8009; Phone (301) 496-5090; Fax (301) 402-0524.

Monoclonal Antibodies Specific for the E2 Glycoprotein of Hepatitis C Virus and Their Use in the Diagnosis, Treatment and Prevention of Hepatitis C

Sun, 01 Apr 2007 14:00:00 GMT
Hepatitis C virus is an enveloped, single stranded RNA virus, approximately 50 nm in diameter, that has been classified as a separate genus in the Flaviviridae family. Most persons infected with hepatitis C virus develop chronic infection. These chronically infected individuals have a relatively high risk of developing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. There is currently no vaccine to prevent the hepatitis C virus infection. The present invention relates to human monoclonal antibodies which exhibit immunological binding affinity for the hepatitis C virus E2 glycoprotein and are cross-reactive against different hepatitis C virus strains. These antibodies may be used in passive immunoprophylaxis for the prevention of hepatitis C virus infection and/or in passive immunotherapy for the treatment of hepatitis C. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these monoclonal antibodies. For more information, please contact Robert H. Purcell, M.D., Co-chief, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 50 South Drive, Bldg. 50, Rm. 6523, Bethesda, MD 20892-8009; Phone (301) 496-5090; Fax (301) 402-0524.

Cyanovirins and Related Conjugates, Compositions, Nucleic Acids, Vectors, Host Cells, Methods of Production and Methods of Use for Microbicide Development

Thu, 01 Mar 2007 19:00:00 GMT
The development of an effective anti-HIV topical microbicide, especially a female-controlled, vaginal microbicide, has been deemed an urgent global priority by numerous international agencies, including the World Health Organization, the U.S. Department of Health and Human Services, the National Institute of Allergy and Infectious Diseases, and others. The present invention provides antiviral proteins (collectively referred to as cyanovirins), conjugates thereof, DNA sequences encoding such agents, host cells containing such DNA sequences, antibodies directed to such agents, compositions comprising such agents, and methods of obtaining and using such agents for the production of microbicides.

Cyanovirin-N (CV-N) potently and irreversibly inactivates diverse primary strains of HIV-1, including M-tropic forms involved in sexual transmission of HIV, as well as T-tropic and dual-tropic forms; CV-N also blocks cell-to-cell transmission of HIV infection. CV-N is directly virucidal, interacting in an unusual manner with the viral envelope, apparently binding with extremely high affinity to poorly immunogenic epitopes on gp120. Further, cyanovirin-N (CV-N) and homologous proteins and peptides potently inhibit diverse isolates of influenza viruses A and B, the two major types of influenza virus that infect humans.

The described technology includes glycosylation-resistant mutants of CV-N, which code sequences to enable ultra large-scale recombinant production of functional cyanovirins in non-bacterial (yeast or insect) host cells or in transgenic animals or plants. Therefore, these glycosylation-resistant mutants may allow industry to produce CV-Ns on a large scale and make CV-Ns cheap enough for developing countries to benefit from this invention.

CV-N was benign in vivo when tested in the rabbit vaginal toxicity/irritancy model, and was not cytotoxic in vitro against human immune cells and lactobacilli (unpublished). CV-N is readily soluble in aqueous media, is remarkably resistant to physicochemical degradation and is amenable to very large-scale production by a variety of genetic engineering approaches. CRADA Opportunity: The National Cancer Institute’s Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize microbicides for HIV and influenza. Please contact John D. Hewes at (301) 435-3121 or hewesj@mail.nih.gov for more information.

Fluorescent Intracellular Calcium Indicators

Fri, 02 Mar 2007 00:00:00 GMT
Calcium is a key element in the regulation of many cellular processes, including muscle contraction, hormone excretion from gland cells, neurotransmitter release from nerve synapses, and the regulation of cellular metabolism. Elevated calcium levels are found in a number of diseases.

The present invention relates to chromophoric or fluorescent dye calcium indicators that are superior for measurement of high concentrations of calcium ions due to their high dissociation constants. As a result of the high calcium ion dissociation constants, the perturbation resulting from introducing the indicator into the cell is greatly reduced. These calcium ion indicators can be measured by various techniques including 19F NMR spectroscopy, flow cytometry, and quantitative fluorescence techniques, and are useful for measuring calcium levels within the cytosol or within cellular organelles. CRADA Opportunity: The NIEHS Laboratory of Structural Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Robert London at 919/541-4879 or london@niehs.nih.gov for more information.

Novel Benzindole Based Compounds for HIV Therapy

Thu, 01 Mar 2007 05:00:00 GMT
The HIV/AIDS epidemic continues despite efforts from scientists, drug companies, and non-profit organizations. Although the existing therapy, is effective in the treatment of many infected individuals in developed nations, the infected individual is not cured and therapy must be life-long. There are problems with drug toxicity, the development of resistant viral strains, and with the cost of therapy. New anti-viral agents are needed for a more effective, and a more cost-effective, treatment of HIV.

The invention describes compounds based on a benzindole moiety, which alkylates DNA. The compounds comprise a benzindole moiety, a bifunctional linker, and a fatty acid residue or dendrimer residue comprising at least one fatty acid. Several benzindole derivatives are synthesized. The compounds bind to the minor groove of DNA and can be useful in the inhibition of gene expression. The advantage of the compounds is that they remain inactive until conformational change induced by DNA binding makes them active. The fatty acid moiety immobilizes them on the cytoplasmic side of the plasma membrane. These anchored compounds are specifically designed to inhibit retroviral DNA before it translocates to the host nucleus and integrates with the host genome. CRADA Opportunity: The National Cancer Institute’s Structural Biophysics Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel benzindole based compounds for HIV therapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Enhanced Function of Gene Modified T-Cells: Identification of T-Cell Receptors (TCR) with Altered Amino Acid Sequence

Thu, 01 Mar 2007 10:00:00 GMT
A major limitation of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Immunotherapy has taken a lead among the new cancer therapeutic approaches. Adoptive immunotherapy is one of the most promising new therapeutic approaches that enhance the innate immunity of an individual to fight against a certain disease.

T cell receptors (TCR) are the proteins responsible for the T cell's ability to recognize infected or transformed cells. TCR consists of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit the recognition signal by interacting with other proteins.

This invention is directed to substitutions in gene sequences that code for T cell receptors, specifically the inventors found that one to two amino acid substitutions in the TCRs that recognize 1G4 XY-ESO-1 and MART-1 resulted in a marked increase of these modified TCRs to recognize tumor cell targets. These mutated sequences are currently being evaluated as candidates for clinical development. The inventors also consider the invention as providing a "general paradigm" that will allow the generation of TCR directed against a variety of antigens that can enhance the function of gene modified T cells. CRADA Opportunity: The NIH Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adoptive immunotherapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Potent Activation of Antigen Presenting Cells by the Hepatitis A Virus Cellular Receptor 1 and Its Role in the Regulation of Immune Responses

Thu, 01 Mar 2007 15:00:00 GMT
Available for licensing and commercial development are compositions and methods to regulate various immune responses through the hepatitis A virus cellular receptor 1 (HAVCR1). HAVCR1 (also known as TIM-1) is a member of the TIM family of receptors that is usurped by the hepatitis A virus (HAV) to infect cells. The gene encoding HAVCR1 has been shown to be an important asthma and allergy susceptibility gene. HAVCR1 plays a critical role in regulating T cell differentiation and the development of atopy. HAVCR1 is over-expressed in kidney ischemic cells and malignant renal tumors. The invention describes a ligand of HAVCR1 in antigen presenting cells (APCs) that is unrelated to murine Tim-4, a TIM family member reported as the ligand of murine Tim-1. The ligand was identified using an expression cloning strategy. The specific binding of HAVCR1 to this ligand on APCs causes activation and induces the expression of co-stimulatory receptors at the cell surface of the APCs and the secretion of cytokines such as IL-6, IL-10, and TNF-a. Furthermore, treatment of APCs with soluble forms of HAVCR1 induced T cell proliferation. The invention describes a novel mechanism by which HAVCR1 regulates immune responses, in which the activation of APCs is mediated by HAVCR1 binding to ligands on APCs. The association of HAVCR1 with the ligand identified in APCs also enhances the interaction of HAVCR1 with HAV. CRADA Opportunity: The Food and Drug Administration, Center of Biologics Research and Evaluation, Laboratory of Hepatitis and Related Emerging Agents, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the hepatitis A virus cellular receptor as a potent activator of antigen presenting cells . Please contact Alice Welch at Alice.Welch@fda.hhs.gov for more information.

Methods of Treating Conditions Characterized by Unwanted or Excessive Presynaptic Neuronal Activity or Secretion

Thu, 01 Mar 2007 20:00:00 GMT
Botulinum toxins are highly potent neurotoxins produced by the spore-forming bacterium, Clostridium botulinum. Poisoning by any of the seven known botulinum toxin serotypes, designated A to G, results in impaired communication between nerve and muscle that causes paralysis in patients and possible death by respiratory failure. Injections of botulinum toxins A and B have been approved for treating disorders associated with uncontrollable muscle contractions. However the use of approved botulinum toxins is limited by their temporary duration of action, the development of neutralizing antibodies after repeated injections, and cross-reactivity with autonomic neurons. Thus, an interest exists in finding new ways to achieve longer-lasting effects using botulinum toxins.

This technology describes a novel method for treating diseases by combining two botulinum toxins, botulinum toxin A and B. Researchers at the FDA have shown that the combination of the A and B toxins is synergistic, improves muscle paralysis characteristics compared to individually administered serotypes, and produces a longer duration of action and a faster onset of paralysis. The synergistic effect allows lower doses compared to single use of either toxin and should help reduce resistance after repeated use. This technology is beneficial for the treatment of diseases already known to be treatable with botulinum toxins, such as facial wrinkles, headaches, muscle spasms, and cervical dystonia. This technology is also suitable to treat other diseases, such as strabismus, hemifacial spasms, facial nerve damage, and hyperhidrosis (excessive sweating).

Available for licensing are methods and pharmaceutical compositions for administering a combination of botulinum toxin A and B to treat unwanted or excessive presynaptic neuronal activity or secretion. CRADA Opportunity: The FDA Center for Biologics Evaluation and Research, Laboratory of Respiratory and Special Pathogens, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact James E. Keller, Ph.D. at 301/402-4418 or kellerj@cber.fda.gov for more information.

Model for Study of Glomerular Disorders: Conditionally-Immortalized Mouse Podocyte Cell Line with Tet-on-Regulated Gene Expression

Fri, 02 Mar 2007 01:00:00 GMT
Podocytes, cells of the visceral epithelium in the kidneys, are a key component of the glomerular filtration barrier. As such, they play a vital role in glomerular disorders, which are a major cause of chronic kidney disease. Examples of these disorders include focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, and diabetic nephropathy.

The inventors have developed a conditionally-immortalized mouse podocyte cell line with tightly controlled conditional gene expression. The cell line has been conditionally immortalized through the introduction of the H-2Kb-tsA58 transgene, which is a temperature-sensitive mutant of the SV40T antigen. Inducible gene expression is tightly controlled through two introduced transgenes, podocin-rtTA and CMV-tTS, that produce a "Tet-on" system wherein gene expression is induced by tetracycline or doxycycline. The combination of the two transgenes for Tet-on gene expression has resulted in much tighter regulation and lower background expression compared to cells carrying the podocin-rtTA transgene alone. CRADA Opportunity: The NIDDK Kidney Disease Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a model system for the study of glomerular disorders. Please contact Jeffrey B. Kopp, M.D., by phone (301/594-3403), fax (301/402-0014) or e-mail (jbkopp@nih.gov) for more information.

Cloning and Characterization of an Avian Adeno-Associated Virus and Uses Thereof

Thu, 01 Mar 2007 06:00:00 GMT
Currently, adeno-associated virus (AAV) represents the gene therapy vehicle of choice because it has many advantages over current strategies for therapeutic gene insertion. AAV is less pathogenic than other virus types; stably integrates into dividing and non-dividing cells; integrates at a consistent site in the host genome; and shows good specificity towards various cell types for targeted gene delivery.

To date, 11 AAV isolates have been isolated and characterized. New serotypes derived from non-human animal species have added to the specificity and repertoire of current AAV gene therapy techniques by avoiding the immunologic complications associated with human isolates.

This invention describes vectors derived from an avian AAV. These vectors have innate properties related to their origin that may confer them with a unique cellular specificity in targeted human gene therapy and a unique immunologic profile that would avoid neutralization by pre-existing antibodies. Therefore, vectors derived from this avian AAV are likely to find novel applications for gene therapy in humans. Furthermore because of their species of origin, this vector would also be useful in the engineering of avian cells. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Laboratory of Dr. John Chiorini, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize gene therapy methods using AAV vectors. Please contact David W. Bradley, Ph.D. at bradleyda@nidcr.nih.gov for more information.

Highly Soluble Pyrimido-Dione-Quinoline Compounds: Small Molecules that Stabilize and Activate p53 in Transformed Cells

Thu, 01 Feb 2007 11:00:00 GMT
The tumor-suppressor p53 protein plays a major role in tumor development. Most human cancers ail to normally activate p53, which is at least partly responsible for the unregulated growth of cancer cells and their failure to undergo apoptosis. While many chemotherapeutics enhance p53 levels, their non-specific DNA damage (genotoxicity) causes unfavorable side effects.

This invention reports the composition and function of a pyrimido-dione-quinoline that was found to inhibit HDM2’s ubiquitin ligase (E3) activity without the accompanying genotoxicity of current therapeutic drugs. Like the HLI98 family of compounds reported previously (see reference below), the subject of the current invention stabilizes p53 in cells, inhibiting its ubiquitin-mediated proteasomal degradation. Unlike the HLI98 compound, the pyrimido-dione-quinoline reported here induces a robust p53 response, and is highly water-soluble. Thus, these pyrimido-dione-quinoline compounds have the potential to stabilize p53 and activate a p53 response in tumors. CRADA Opportunity: The Laboratory of Protein Dynamics and Signaling (LPDS) at the National Cancer Institute, NIH, is seeking a collaborative partner under a Cooperative Research and Development Agreement (CRADA) to develop therapeutics approaches utilizing inhibitors of the ubiquitin system such as described in this invention. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Broadly Cross-Reactive Neutralizing Antibodies against Human Immunodeficiency Virus Selected by ENV-CD4-CO-Receptor Complexes

Thu, 01 Feb 2007 16:00:00 GMT
This invention provides a novel anti-HIV human monoclonal antibody named X5. This antibody demonstrates promise over conventional anti-HIV antibodies because the X5 antibody exhibits a unique binding activity compared to its counterparts. It has been established that the initial stage of HIV-1 entry into cells is mediated by a complex between the viral envelope glycoprotein (Env) such as gp120-gp41, a receptor CD4 and a co-receptor CCR5. The X5 antibody binds to an epitope on gp120 that is induced by interaction between gp120 and the receptor CD4 and enhanced by the co-receptor CCR5. The X5 antibody also shows strong activity at very low levels (in the range from 0.0001 - 0.1 Mg/ml concentration is dependent on the isolate). Because it is a human antibody, it can be administered directly into patients so that it is an ideal candidate for clinical trials. It also can be easily produced because it was obtained by screening of phage display libraries and its sequence is known. Finally, since it has neutralized all virus envelope glycoproteins, including those from primary isolates of different clades, the epitope is highly conserved and resistance is unlikely to develop. Therefore, this antibody and/or its derivatives including fusion proteins with CD4 are good candidates for clinical development.

Additional information on the current research in Dr. Dimitrov's laboratory may be found at http://www-lecb.ncifcrf.gov/~dimitrov/dimitrov.html. CRADA Opportunity: The NCI Center for Cancer Research Nanobiology Program (CCRNP) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize antibodies for HIV research, diagnostics and therapeutic development. Please contact John D. Hewes, Ph.D. at (301) 435-3121 or hewesj@mail.nih.gov for more information.

Human Cancer Therapy Using Engineered Anthrax Lethal Toxin

Thu, 01 Feb 2007 21:00:00 GMT
Anthrax lethal toxin (LeTx) consists of two components: the protective antigen (PrAg) and the lethal factor (LF). PrAg binds to the cell surface where it is activated by furin protease, followed by the formation of a PrAg heptamer. LF is then translocated into the cytosol of a cell via this heptamer, where it acts as a metalloprotease on all but one mitogen-activated protein kinase kinase (MAPKK). Approximately 70% of human melanomas contain a mutation (B-RAF V600E) that constitutively activates a MAPKK pathway, and LeTx has been shown to have significant toxicity towards cells which have this mutation. This suggested a potential use for LeTx in cancer therapy. Unfortunately, native LeTx is toxic to normal cells, detracting from its in vivo applicability.

PrAg has been engineered to be activated by a matrix metalloprotease (MMP), instead of by furin protease. Because MMPs are highly expressed in tumor cells, this modification increases selectivity towards cancer cells. Surprisingly, mouse data shows that the modified LeTx (denoted PrAg-L1/LF) is less cytotoxic to "normal" cells in vivo, when compared to wild-type LeTx. Significantly, PrAg-L1/LF maintained its high toxicity toward human tumors in mouse xenograft models of human tumors, including melanomas. However, this toxicity applied not only to tumors having mutations that constitutively activate MAPKKs, but also to other tumor types such as lung and colon carcinomas. The absence of toxicity to "normal" cells coupled to its effectiveness on a wide range of cancer cell types suggests that PrAg-L1/LF may represent a novel cancer therapeutic. CRADA Opportunity: The NIAID Laboratory of Bacterial Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize PrAg-L1/LF as a novel cancer therapeutic. Please contact Stephen H. Leppla, Ph.D. at 301/594-2865 and/or sleppla@niaid.nih.gov for more information.

Chemokine-Tumor Antigen Fusion Proteins as Cancer Vaccines

Fri, 02 Feb 2007 02:00:00 GMT
Available for licensing is a tumor vaccine construct comprising a chemoattractant (such as human chemokines CCL7 and CCL20) fused to a tumor antigen (including human mucin-1, a transmembrane protein that is aberrantly expressed in cancer; or single chain antibody expressed by B cell malignancy, or melanoma antigen gp100 expressed in human melanomas). The majority of tumor antigens are believed to be poorly immunogenic because they represent oncogene gene products or other cellular genes which are normally present in the host. As a result, poor immunogenicity has been a major obstacle to successful immunotherapy with tumor vaccines. Administration of this fusion chemokine and tumor antigen protein, or a nucleic acid encoding this fusion protein, elicits a tumor specific cellular and humoral immune response thereby providing a potent cancer vaccine. CRADA Opportunity: The National Institute on Aging, Laboratory of Immunology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cancer vaccines that target skin antigen-resenting cells. Please contact Nicole Guyton at 301-435-3101 or guytonn@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Enriched Natural Killer Cells for Adoptive Infusion Cancer Therapy

Mon, 01 Jan 2007 07:00:00 GMT
Immuno-therapy has taken a lead among the new cancer therapeutic approaches. It is one of the most promising new therapeutic approaches that exploit the innate immune mechanism of an individual to fight against a certain disease.

Natural killer (NK) cells are a form of cytotoxic lymphocytes which constitute a major portion of the innate immune system. NK cells have tumor cytotoxic properties independent of tumor specific antigens and have been shown in murine models to control and prevent tumor growth and dissemination. Inactivation of NK cells potentially allows cancer cells to evade host NK-cell-mediated immunity. Ligation of killer immunoglobulin like receptors (KIRs) by MHC class I on both normal and malignant tissues suppresses the function of NK cells.

The present invention relates to treating cancer and other hyperproliferative disorders by administering an enriched composition of allogeneic or autologous (KIR/KIR ligand incompatible) NK cell population. This enriched composition can potentially override the inactivation of NK cells by self HLA molecules or MHC class I expressing tumors. Claims cover compositions of enriched NK cell populations and method of treating malignancies or prevent recurrence of malignancies and treating any hyperproliferative disorders with these enriched compositions. Claims also cover a method to sensitize malignancies to NK cell TRAIL-mediated killing by pretreatment with bortezomib. CRADA Opportunity: The Hematology Branch of the National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of in vitro expanded adoptively infused NK cells to treat advanced and incurable cancers. Please contact Dr. Richard W. Childs at 301/496-5093 or 301/451-7128 (email: childsr@nih.gov) for more information.

A New Method for Improving the Therapeutic Efficacy of L-Asparaginase in Multiple Types of Cancer

Mon, 01 Jan 2007 12:00:00 GMT
For the last several decades, L-asparaginase (L-ASP) has been widely used as a clinical treatment for leukemias. Studies show that cancer cells that contain less asparagine synthetase (ASNS) are more susceptible to L-ASP. The response to L-ASP therapy is often better when the expression of ASNS is limited.

The present invention describes a new method for enhancing L-ASP activity by combining it with antagonists of ASNS – such as siRNAs, antisense nucleotides, antibodies or small-molecule inhibitors – for treatment of cancers. Reducing or suppressing the expression of ASNS potentiates the growth inhibitory activity of L-ASP.

Additionally, the invention discloses a novel biomarker screening tool to identify leukemia, ovarian, and other cancer patients that would be most likely to respond to L-ASP treatment. CRADA Opportunity: The National Cancer Institute’s Genomics & Bioinformatics Group in the Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the combination therapies described in this abstract. Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.

Macrocyclic Grb2 SH2 Domain-Binding Inhibitors: New Anti-cancer and Anti-angiogenic Therapeutic Agents

Mon, 01 Jan 2007 17:00:00 GMT
Growth factor receptor bound 2 (Grb2) SH2 domain is involved in signaling events leading to a variety of proliferative diseases including erb-2 dependent breast cancers and c-met dependent renal cancers. Inhibiting the Grb2 SH2 domain binding has great potential therapeutic utility in the treatment of certain cancers.

This technology discloses the design and synthesis of new macrocyclic inhibitors of Grb2 SH2 domain binding. More specifically, a simple synthetic approach using upper achiral junctions has been utilized that does not require complex stereoselective synthesis. These new series of compounds have synthetic advantage over similar macrocyclic compounds and retain good binding affinity towards Grb2 SH2 domain. CRADA Opportunity: The National Cancer Institute Laboratory of Medicinal Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize macrocyclic Grb2 SH2 domain-binding antagonists. Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.

Fast Electron Paramagnetic Resonance Imaging (EPRI) Using CW-EPR Spectrometer with Sinusoidal Rapid-Scan and Digital Signal Processing

Mon, 01 Jan 2007 22:00:00 GMT
Electron Paramagnetic Resonance (EPR) Imaging is an indispensable tool that may be applied to a variety of disciplines for evaluation of chemical species having unpaired electrons such as free radicals and transition metal ions. In Continuous Wave (CW)-EPR the sample is continuously irradiated with weak RF radiation while sweeping the magnetic field relatively slowly. Existing CW-EPR techniques utilize a signal detection method known as phase-sensitive detection which results in data acquisition times that are too long for in vivo applications. The present technology represents significant improvements on conventional CW-EPR.

The subject technology includes three approaches to collecting image data with increased spatial, temporal and spectral resolution and improved sensitivity. Spectral data acquisition is performed by a direct detection strategy involving mixing a signal to base-band and acquiring data with a fast-digitizer. Projection data is acquired using a sinusoidal magnetic field sweep under gradient magnetic fields. Data collection times are decreased with the utility of rotating gradients.

Further improvement to the present technology includes optimized DSP (digital signal processing) transmit and receive systems that decrease the analog background noise and allow optimizing the extent of signal averaging for improved image quality.

Increased speed and sensitivity make CW-EPR a potentially useful and complementary tool to proton Magnetic Resonance Imaging for in vivo imaging. The presently described improvements to CW-EPR will allow changes of blood perfusion and oxygenation in tumors to be observed in nearly real-time, while improved resolution will permit angiogenesis in and around tumors to be monitored in a non-invasive manner. Additionally, rapid scan imaging provides excellent temporal resolution and will help quantify pharmaco-kinetics and metabolic degradation kinetics of bioactive and redox sensitive free radicals such as nitroxides. CRADA Opportunity: The National Cancer Institute, Radiation Biology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop improved hardware in terms of higher gradient & sweep frequencies and compatible AC amplifiers and evaluate, or commercialize the above rapid scan-rotating gradients strategy for performing routine in vivo radiofrequency CW EPR imaging in small animals. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

In vivo Assessment of Tissue Microstructure and Microdynamics: Estimation of the Average Propagator from Magnetic Resonance Data

Tue, 02 Jan 2007 03:00:00 GMT
This invention relates to diffusion-weighted magnetic resonance imaging (DW-MRI) and describes a novel method for estimating the 3-D average propagator from DW-MRI data. The average propagator measures the probability that water molecules move from one place to another during a given diffusion time. This quantity provides local information about the tissue microstructure and the microenvironment in which water diffuses without making any a priori assumptions about the underlying diffusion process itself. Several methods, such as 3D q-space magnetic resonance imaging (MRI) and diffusion spectrum imaging have been developed to measure the average propagator, but these techniques currently require acquisition of large numbers of DW images, making them infeasible for routine animal and clinical imaging. The proposed methodology introduces a new data reconstruction concept, which involved using computer tomography (CT) algorithms to estimate the average propagator from the MR data. The proposed CT reconstruction requires many fewer DW-MRI data than conventional methods consistent with a clinically feasible period of MR image acquisition. The novel technique can be used to diagnose medical disorders that are associated with alterations in water diffusion, such as stroke and several neurodegenerative diseases and other disorders for which diffusion tensor MRI is currently used. Additional applications include drug development (screening drug candidates), material science (testing the quality of materials that have restricted and hindered compartments, e.g., porous media, gels and films) and food processing (testing structural changes in food). CRADA Opportunity: The NICHD Laboratory of Integrative and Medical Biophysics, Section on Tissue Biophysics and Biomimetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Peter J. Basser, Ph.D. at pjbasser@helix.nih.gov for more information.

Novel Benztropine Analogs for Treatment of Cocaine Abuse and Other Mental Disorders

Mon, 01 Jan 2007 08:00:00 GMT
Dopamine is a neurotransmitter that exerts important effects on locomotor activity, motivation and reward, and cognition. The dopamine transporter (DAT) is expressed on the plasma membrane of dopamine synthesizing neurons, and is responsible for clearing dopamine released into the extra-cellular space, thereby regulating neurotransmission. The dopamine transporter plays a significant role in neurotoxicity and human diseases, such as Parkinson’s disease, drug abuse (especially cocaine addiction), Attention Deficit Disorder/Attention Deficit Hyperactivity Disorder (ADD/ADHD), and a number of other CNS disorders. Therefore, the dopamine transporter is a strong target for research and the discovery of potential therapeutics for the treatment of these indications.

This invention discloses novel benztropine analogs and methods of using these analogs for treatment of mental and conduct disorders such as cocaine abuse, narcolepsy, ADHD, obesity and nicotine abuse. The disclosed analogs are highly selective and potent inhibitors of DAT, but without an apparent cocaine-like behavioral profile. In addition to their use as a treatment for cocaine abuse, these compounds have also shown efficacy in animal models of ADHD and nicotine abuse, and have also been shown to reduce food intake in animals. They may also be useful medications for other indications where dopamine-related behavior is compromised, such as alcohol addiction, tobacco addiction, and Parkinson’s disease. CRADA Opportunity: The Medicinal Chemistry and Psychobiology Sections, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize medications to treat cocaine abuse and addiction. Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.

Chitosan as a Universal Vaccine Adjuvant, Antigen Depot and Cytokine Depot

Fri, 01 Dec 2006 13:00:00 GMT
This technology describes the use of chitosan depots with appropriate antigens and/or cytokines for generating an immune response in a subject. Such depots are made by mixing one or more antigens and/or cytokines with chitosan or a chitosan derivative. Similar compositions are described wherein chitosan or a derivative forms a micro- or nanoparticle, which have resulted in a more immunogenic presentation of antigen compared to antigen in solution. Using a representative antigen, the inventors showed that mice vaccinated with the subject depots had increased humoral and cellular immune responses compared to mice vaccinated with antigen alone¹. Furthermore, comparative mouse studies showed the antigen-specific immune response generated with chitosan depots of this invention to be equipotent to incomplete Freund's adjuvant (IFA) and superior to aluminum hydroxide, a widely used adjuvant for licensed and routinely administered vaccines¹. Thus, this technology improves upon commonly used adjuvant technology and is widely applicable. This technology is the first to show that subcutaneous administrations of chitosan and an appropriate antigen, with no other component, can be used for enhancing immune responses. In additional studies, the inventors showed that chitosan is able to maintain a depot of recombinant cytokine. A single subcutaneous injection of chitosan-cytokine outperforms daily injections of recombinant cytokine in both the expansion of draining lymph nodes and in the antigen presenting ability of lymph node cells. This technology is the first to show that chitosan can maintain a depot of cytokine which results in a significant enhancement of the functional effects of a cytokine. This technology can be used for vaccines and immunotherapies against various infectious agents and cancer. CRADA Opportunity: The NCI Laboratory of Tumor Immunology and Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize chitosan-mediated immunopotentiation of vaccines and immunotherapies. Please contact John Hewes, Ph.D. at 301-496-0477 or hewesj@mail.nih.gov for more information.

Production, Recovery and Purification Process for Plasmid DNA Clinical Manufacturing

Fri, 01 Dec 2006 18:00:00 GMT
Available for licensing from NIH is a method for large scale production, recovery, and purification process for plasmid DNA manufacturing meeting human clinical trial requirements. DNA plasmid recovery and purification methods can separate plasmid from contamination from a variety of sources including cellular debris and proteins as well as genomic DNA and RNA. Traditionally, DNA plasmid recovery methods utilizing column chromatography have had poor results such as product elutes with broad smears rather than sharp peaks, product elutes appearing in the flow through thereby preventing isolation from lysate components, and monomeric supercoiled plasmids are not separated from other forms of plasmids. To overcome these shortcomings, a fermentation, recovery, purification, and formulation process for the production of plasmid has been developed. The overall recovery of this process is greater than 400 mg of formulated final product per kilogram (wet weight) of E. coli cell paste. CRADA Opportunity: The National Cancer Institute - Frederick is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize A Production, Recovery and Purification Process for Plasmid DNA Clinical Manufacturing. Please contact John Hewes, Ph.D. at 301-496-0477 or hewesj@mail.nih.gov for more information.

Novel Treatments for Autoimmune Neuroinflammatory Diseases including Multiple Sclerosis

Fri, 01 Dec 2006 23:00:00 GMT
Multiple sclerosis is caused when T cells mistakenly attack myelin, the protective fatty layer surrounding neurons in the brain and spinal cord, to initiate autoimmune responses and inflammation of the central nervous system (CNS). An increase in T cell-endothelial cell interactions and/or increased infiltration of immune cells to the CNS may play a role in the onset and/or progression of this disease.

Researchers at the NIH previously reported that extracellular adherence protein (Eap) produced by Staphylococcus aureus interacts with intercellular adhesion molecule 1 to prevent beta2-integrin-dependent inflammatory cell recruitment. They have now shown that Eap administration to mice with experimental autoimmune encephalomyelitis, a condition thought to be a model for human multiple sclerosis, blocks T cell recruitment to the brains of the EAE affected mice, inhibits the onset of this disease, and reverses paralysis. Eap also reduces delayed-type hypersensitivity in affected mice by inhibiting T cell infiltration and plasma leakage.

Available for licensing are methods for administering an Eap agent in an amount that will treat or prevent autoimmune neuroinflammatory diseases such as multiple sclerosis, decrease the infiltration of immune cells to the central nervous system, and inhibit T cell-endothelial cell interactions. CRADA Opportunity: The National Cancer Institute Experimental Immunology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Novel Treatments for Autoimmune Neuroinflammatory Diseases including Multiple Sclerosis. Please contact John Hewes, Ph.D., at 240-482-3453 for more information.

Extracellular Matrix/Metastasis Modifier Genes as a Method for Characterization and Prevention of Metastatic Tumor

Sat, 02 Dec 2006 04:00:00 GMT
To a large extent cancer mortality is due to metastatic disease than a primary tumor. Recent evidence suggests that metastatic disease can be an early event and in majority of patients metastasis starts by the time the disease is diagnosed. Thus there is a need for methods of characterizing the early metastatic process for better treatment of cancer.

This invention provides methods of characterizing the metastatic capacity of a tumor as well as inhibiting metastasis of a cancer cell. More specifically, this invention discloses an extracellular matrix (ECM) modifier protein named Anakin, detection of the Anakin protein as a marker for metastatic disease and use of Anakin as potential therapeutic target. CRADA Opportunity: The NCI Laboratory of Population Genetics is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of Anakin as a prognostic tool for diagnosing breast cancer outcome. Please contact John Hewes, Ph.D., at 301-435-3121 for more information.

Peptide and Peptidomimetic Inhibitors of Smoothened Protein as Anti-neoplastic Agents

Fri, 01 Dec 2006 09:00:00 GMT
Cancer is caused by the improper regulation of certain signaling proteins in the cell. One of these pathways is the Hedgehog/Patched (HH/PTCH) pathway. Hedgehog is a secreted protein involved in the growth and development of embryonic cells. Patched is the receptor for hedgehog proteins and regulates a membrane protein called Smoothened (SMO). This pathway is activated in many tumor cells, including those in prostate, pancreas, stomach, and small cell cancer.

The technology is directed towards several synthetic peptides (including all-D analogs) corresponding to specific region of the SMO protein. Experiments in vitro demonstrate that they potentially suppress the growth of cancer cells and inhibit the expression of the HH/PTCH pathway genes. These novel SMO inhibitors are much more effective in inhibiting cell growth than currently available cyclopamine and cyclopamine derivatives. These novel peptides and their metabolically more stable analogs have a high potential for cancer therapy. Due to their high hydrophobic properties, these can be easily formulated for specific intratumor delivery or topical creams for skin disorders. CRADA Opportunity: The NCI-Frederick Structural Biophysics Laboratory is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Peptide and Peptidomimetic Inhibitors of Smoothened Protein as Anti-neoplastic Agents. Please contact John Hewes, Ph.D., at 240-482-3453 for more information.

Small Molecules for Imaging Protein-Protein Interactions

Fri, 01 Dec 2006 14:00:00 GMT
Imaging techniques like positron emission tomography and photon emission computerized tomography are often used with imaging agents to detect the presence and accumulation of amyloid plaques within the human brain. These imaging agents have high specificity for beta amyloid peptides, and administration of such agents aids in the early detection of amyloid plaques in brains of Alzheimer's victims. However, currently available imaging agents have limited success for detecting pre-plaque beta amyloid proteins because they are small and reside within the tissue for a short period of time. Therefore, new imaging agents are needed for enhanced identification of amyloid deposits.

Available for licensing and commercial development are small molecules for imaging protein-protein interactions in Alzheimer's disease. This technology describes a bifunctional molecule with high specificity for beta amyloid proteins that is applicable for in vivo imaging. The molecule contains two moieties with different binding affinities, one moiety has an affinity for amyloid beta proteins, and the other moiety has an affinity for a tissue-specific chaperone. The different moieties of the subject invention are conjoined by an inert linkage group, typically comprised of a hydrocarbon chain, peptide, or carbohydrate. The subject invention is affixed with a label, such as a fluorophore or radioisotope, which adheres to the binding site of the beta amyloid protein, the chaperone, or the linkage group. The choice of label makes the subject invention versatile and employable in several types of imaging modalities such as single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and computerized tomography (CT) scans. CRADA Opportunity: The National Institutes of Health Clinical Center, Laboratory of Diagnostic Radiology Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Small Molecules for Imaging Protein-Protein Interactions. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Method for Producing Significant Amounts of B19 Virus for Development of Killed or Attenuated Vaccines

Fri, 01 Dec 2006 19:00:00 GMT
Human parvovirus B19 (B19) is a common infection of children and adults and is the cause of fifth disease. B19 selectively infects erythroid progenitor cells of bone marrow, fetal liver and a small number of specialized cell lines. These specific cell lines demonstrate limited infectibility and commonly produce little or no virus following initial inoculation with B19. Current methods for producing infectious B19 require phlebotomy of infrequently available infected donors. The available technology describes a method of producing pure populations of human erythroid progenitor cells that are fully permissive to B19 infection. The ability to efficiently generate significant amounts of infectious B19V in cells is useful for the development of killed or attenuated vaccines, therapeutics and efficient diagnostic tools for prevention and treatment of B19V. CRADA Opportunity: The NHLBI Hematology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel methods to produce parvovirus B19 and use as diagnostic or vaccine. Please contact Dr. Neal Young at 301-496-5093, YoungNS@mail.nih.gov for more information.

Antisera to Detect Phosphorylated Phosphoinositide-Dependent Kinase 1 (PDK-1)

Sat, 02 Dec 2006 00:00:00 GMT
PDK-1 phosphorylates and activates a number of cellular kinases, and plays a major role in insulin and growth factor signaling. PDK-1 also represents a promising drug target for a number of cancers. Autophosphorylation at Ser244 (mouse) or Ser241 (human) is critical for PDK-1 activity.

Available for licensing are polyclonal rabbit antisera that specifically detect mouse PDK-1 protein phosphorylated at Ser244. These antisera are also expected to be specific for the human PDK-1 protein phosphorylated at Ser241. CRADA Opportunity: The NIH, NCCAM, Diabetes Unit is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize phospho-specific PDK-1 antibody and insulin signaling. Please contact Michael J. Quon, Chief, Diabetes Unit, NCCAM, NIH at quonm@nih.gov for more information.

ARH3, a Therapeutic Target for Cancer, Ischemia, and Inflammation

Fri, 01 Dec 2006 05:00:00 GMT
ADP-ribosylation is important in many cellular processes, including DNA replication and repair, maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. Poly-ADP-ribose is important in a number of critical physiological processes such as DNA repair, cellular differentiation, and carcinogenesis. Until recently, only one human enzyme, PARG, had been identified that degrades the ADP-ribose polymer. Another ADP-ribose, O-acetyl-ADP ribose, is formed via the deacetylation of proteins, such as acetyl-histone, by proteins in the Sir2 family. Sir2 proteins have been implicated in regulation of chromatin structure and longevity.

The NIH announces the discovery of a novel PARG-like enzyme, ARH3. ARH3 possesses PARG activity, yet is structurally distinct from PARG. ARH3 also hydrolyzes O-acetyl-ADP-ribose, and is the only protein recognized to date with such activity. ARH3 thus appears to function in two important signaling pathways, serving to regulate both poly-ADP-ribose and O-acetyl-ADP-ribose levels. It may affect chromatin structure through effects on both pathways. Since ARH3 structures differs from PARG or other enzymes that participate in these pathways, it may be possible to design specific inhibitors to target both the poly-ADP-ribose and Sir2 pathways. These drugs may be used as anticancer agents, radiosensitizers or antiviral agents, or for treating disorders involving oxidative damage, such as acute tissue injury, ischemia, and inflammation. CRADA Opportunity: The Pulmonary Critical Care Medicine Branch in the National Heart, Lung, and Blood Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the invention. Please contact Brian W. Bailey, Ph.D. at 301-594-4094 or bbailey@mail.nih.gov for more information.

Noncovalent HIV Env-CD4 Complexes as HIV Vaccines

Fri, 01 Dec 2006 10:00:00 GMT
HIV vaccine technology based on HIV envelope protein (Env) have been less successful than anticipated to date. One possible reason for this is the potential conformational masking of neutralizing epitopes. The current technology combines HIV Env and cell surface polypeptides CD4 in non-covalent complexes to expose epitopes not present on the uncomplexed Env molecules. These complexes can thus be used to elicit neutralizing antibodies when used as vaccines, immunogenic compositions or immunotherapies. The CD4 inducing epitopes found in regions of the virus that are most conserved across clades are unmasked and immune sera generated with this technology neutralized primary HIV-1 viruses from several clades. Additionally, cell surface polypeptide CD4 is in its native conformation and masked by Env, therefore it is unlikely to induce autoantibodies. CRADA Opportunity: The FDA Center for Drug Evaluation and Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this HIV Env-CD4 technology. Please contact Beatrice A. Droke at 301/827-7008 or bea.droke@fda.hhs.gov for more information.

Modified Bacterial Strain for Otitis Media Vaccine

Fri, 01 Dec 2006 15:00:00 GMT
This invention relates to a strain of Moraxella catarrhalis containing a gene mutation that prevents endotoxic lipooligosaccharide (LOS) synthesis and potential use of the mutant for developing novel vaccines against the pathogen, for which there is currently no licensed vaccine. M. catarrhalis is one of the causative agents of otitis media (middle ear infection), sinusitis, and lung infections. The mutant is defective in the lpxA gene, whose enzyme product is relevant in lipid A biosynthesis (lipid A is part of the LOS). The nontoxic mutant was found to elicit high levels of antibodies with bactericidal activity and provided protection against wild type bacterial challenge. Use of this mutant bacterium is envisioned as a new approach for vaccines against M. catarrhalis. CRADA Opportunity: The Vaccine Research Section in the National Institute on Deafness and Other Communication Disorders (NIDCD) is seeking statements of capability or interest from parties interested in collaborative research. NIDCD is interested in developing outer membrane proteins (OMP), outer membrane vesicle (OMV), and whole cell vaccines generated from the mutant. The mutant strain can also be used as an effective vehicle to express and deliver protective antigens from other important human pathogens. Please contact Dr. Xin-Xing Gu by phone (301/402-2456) or email (guxx@nidcd.nih.gov) for more information.

Sample Delivery System with Laminar Mixing for Microvolume Biosensing

Fri, 01 Dec 2006 20:00:00 GMT
The invention is a sample delivery system with at least two microchannels connected to a sample chamber containing a biosensor. Biosensing for studying molecular recognition has become an important biophysical tool for biomedical research. The system aspirates a small sample volume into the microfluidic channels and applies a periodic oscillatory flow pattern to the sample. This prevents sample depletion in the stagnant layer across the sensor surface and results in efficient mixing of the sample during the biosensor measurement. Because the oscillatory flow pattern does not produce a net transport of the sample with time, there is a very long incubation time of the sensor surfaces with a very small sample volume. The new sample delivery system uses sample volumes of only 3 to 8 microliters, compared to the 25 to 200 microliter volumes of conventional systems, which use cuvette principles or continuous flow microfluidics. The present invention is substantially better than existing systems with respect to biosensor contact time and required sample volume.

CRADA Opportunity: The NIH Office of Research Services, Division of Bioengineering and Physical Science, Protein Biophysics Resource, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this Sample Delivery System technology. Please contact Dr. Peter Schuck at 301/435-1950 or pschuck@helix.nih.gov for more information.

Preparative Two Dimensional Gel Electrophoresis System

Sat, 02 Dec 2006 01:00:00 GMT
The National Institute of Environmental Health Sciences has developed procedures and a prototype device for isolation of proteins from complex mixtures for protein identification. The system serves as a one-step purification method for isolation of biologically relevant proteins affected by disease or experimental treatment and has been described in Electrophoresis 15, 735–745, 1994. The system includes a preparative isoelectric focusing device for separation of proteins by charge, a glass mold for preparative polyacrylamide gel separation by mass and a protocol for use.

The commercial advantage of the Preparative Two Dimensional Gel Electrophoresis system is to separate and isolate sufficient amounts of individual protein for sequencing in a powerful one-step purification method. The Preparative Two Dimensional Gel Electrophoresis system can resolve individual proteins by charge and mass from up to 1 to 2 mg of unpurified starting material from protein mixtures. Current devices for two dimensional gel electrophoresis are generally for analytical scale work and are not physically or procedurally adapted to accommodate preparative sample loads. Although other preparative electrophoresis devices do exist, they separate by either mass or charge alone and function as stand-alone units without ready integration into additional systems for resolution of individual proteins. CRADA Opportunity: The NIEHS National Center for Toxicogenomics, Proteomics Group, may consider statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this preparative two-dimensional gel electrophoresis system. Please contact John Penta, NIEHS Office of Translational Research, at 919/541-3696 or penta@niehs.nih.gov for additional information.

Systems and Methods for Intelligent Quality Control of Instruments and Processes

Fri, 01 Dec 2006 06:00:00 GMT
Available for licensing and commercial development is a cost-effective system and method for evaluation of instruments and processes for real-time detection of error. The subject invention includes the capacity to identify imprecision in a variety of data analysis tools, which may be susceptible to malfunction. Such processes include instrumental analysis of patient specimens, assembly line manufacturing and general plant or factory operation. This system provides an automated platform for the dual purpose of 1) monitoring data to detect unusual events in real time and 2) enhancement of human and machine recognition and analysis of improper occurrences based on time-varying patterns of measured values.

The scheme of the current system is straightforward and in general the method involves the following steps: 1) collection of data elements from an instrument or process 2) counting data elements having values within predetermined intervals of the data range 3) applying counts of data to a neural network that monitors data trends and 4) production of an output based on the neural network, which demonstrates whether the instrument or process is generating results within an appropriate range. This system is advantageous because output is generated in real time and thus available without delay for immediate correction of malfunctions. CRADA Opportunity: The National Institutes of Health Clinical Center, Radiologic and Imaging Sciences, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Intelligent Quality Control of Instruments. Please contact Elaine Ayres at 301/594-3019 for more information.

Second Generation Nitric Oxide-releasing Non-steroidal Anti-inflammatory Drugs Possessing a Diazeniumdiolate Group (NONO-NSAIDs)

Wed, 01 Nov 2006 10:00:00 GMT
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most useful clinical therapies for the treatment of pain, fever and inflammation. It is estimated that more than 30 million people take NSAIDs every day. However, the major mechanism by which NSAIDs exert their anti-inflammatory activity is also responsible for the gastrointestinal, renal and hepatic side effects observed in patients undergoing long-term treatment of chronic conditions. The most common side effects associated with NSAID administration are gastroduodenal erosions and ulcerations affecting around 15% of chronic NSAID users. While many of these clinical manifestations are mild, they may develop into serious events such as bleeding, perforation, obstruction, and sudden death. Therefore, the gastric irritant effect of NSAIDs (particularly aspirin) can be a deterrent to its long-term use for the prophylactic prevention of adverse cardiovascular events such as stroke and myocardial infarction, or as a safe chemopreventive agent to avoid the recurrence of colorectal cancer (CRC).

One of the main strategies that have emerged to improve the safety profile of NSAIDs is the linkage of a nitric oxide (NO)-releasing moiety to the structure of classical NSAIDs (NO-NSAIDs). However, all NO-releasing NSAIDs published so far have a nitrooxyalkyl group as the NO-releasing group. An important drawback to this design is the fact that production of NO (only one equivalent) from organic nitrate esters requires a metabolic three-electron reduction in vivo, and this activation decreases in efficiency on continued use of the drugs, contributing to "nitrate tolerance".

This invention describes the design, synthesis and biological evaluation of novel NO-releasing non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) possessing a N-diazen-1-ium-1,2-diolate (NONOate), which offers additional advantages compared with organic nitrate-based NO-NSAIDs:

Simultaneous release of the corresponding NSAID and NO.

Production of two equivalents of NO (twice as much) by a first-order rate.

Metabolic activation (hydrolysis) mediated by non-specific esterases, which unlike redox metabolism, is not expected to produce tolerance upon long-term treatment.

CRADA Opportunity: The Chemistry Section of the Laboratory of Comparative Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the prodrugs described, as new and safer analgesic, anti-inflammatory, anti-thrombotic, and cancer chemopreventive agents. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Anti-H5N1 Influenza Activity of the Antiviral Protein Cyanovirin

Wed, 01 Nov 2006 14:00:00 GMT
Influenza A viral subtype H5N1 causes avian influenza and is currently the subject of increasing international attention. Usually, avian influenza infection is limited to birds and pigs; however H5N1 has the unique capacity to bring about severe illness and death in humans. H5N1 is highly contagious, fast spreading and rapidly evolving and therefore has the potential to cause a worldwide health epidemic.

The available technology embodies methods of using a cyanovirin-N (CV-N) peptide, protein, or nucleic acid in the prevention and/or treatment of infection. Methods, which utilize CV-N in the treatment of certain influenza strains, have previously been demonstrated. However, the novel use of CV-N to treat the H5N1 strain is unique and development of prophylactics and/or therapeutics against the virus represents a significant contribution to agriculture and public health sectors throughout the world. CRADA Opportunity: The NCI Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cyanovirin-N for use against H5N1 influenza. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Simian Immunodeficiency Virus Expressing HIV-1 Reverse Transcriptase for the Study of Antiviral Drug Resistance in Macaques

Wed, 01 Nov 2006 18:00:00 GMT
Antiviral drug-resistance is the primary source for the decreased efficacy of currently available human immunodeficiency virus-1 (HIV-1) therapies. The available material provides a model system in which to test new antiviral treatment efficacy as well as the development of multi-drug-resistance to HIV-1 reverse transcriptase inhibitors, which is a widespread obstacle of existing antiretroviral therapies. This invention describes a simian immunodeficiency virus (SIV) that expresses HIV-1 reverse transcriptase. The available virus infects and replicates in macaques and has demonstrated use in the study of drug-resistance in an animal model. This technology represents an advantage over traditional SIVs, which are not susceptible to FDA-approved antiretroviral drugs and as a result cannot be used to study HIV drug-resistance in animals. Thus, the current research tool provides a novel resource for advancing the study of drug-resistance to antiretroviral therapy and has the potential to contribute to the development of innovative therapeutic agents that are successful against drug-resistant HIV strains. CRADA Opportunity: The National Cancer Institute’s HIV Drug Resistance Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize animal models in which to evaluate anti-HIV-1 therapy. Please contact Betty Tong, Ph.D. at 301-594-4263 or tongb@mail.nih.gov for more information.

HSV-2 Diagnostic

Wed, 01 Nov 2006 22:00:00 GMT
The present invention relates to novel diagnostic methods for Herpes Simplex Virus Type 2 (HSV-2). HSV-2 infects approximately one fifth of adults in the United States and is the most common cause of genital ulceration. The invention relates to the detection of HSV-2 based on a transforming nucleic acid sequence and its protein product. This DNA sequence harbors the potential to induce the tumorigenic transformation of normal cells in in vitro and in vivo assays and thus will be useful as a means of prognostic evaluation in predicting the development of genital or cervical cancer. Current HSV-2 diagnostic tests relying on tedious viral culture and/or immunoassays that do not have the sensitivity and the specificity essential for diagnosis. Using PCR, the current invention will provide a superior method for viral detection and subtyping. CRADA Opportunity: The NCI Division of Basic Science is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HSV-2 Diagnostic. Please contact Betty Tong, Ph.D. at 301-594-4263 or tongb@mail.nih.gov for more information.

PDE11A as a Novel Therapeutic Target for Inherited Form of Cushing Syndrome and Endocrine Tumors

Mon, 02 Oct 2006 02:00:00 GMT
Cushing Syndrome, a disorder associated with excess production of a steroid hormone, cortisol, affects up to 10 per 15 million people every year. Cushing Syndrome may be caused by several reasons such as cortisol-producing endocrine tumors and can be inherited in some instances. Surgery of the adrenal tumor is the most common method of treatment. New diagnostic and therapeutic approaches need to be developed for successful management of the disease.

This technology describes the clinical identification of a new disease termed “isolated micronodular adrenocortical disease” (iMAD), as well as the role of PDE11A gene in this disease. Additionally, the technology also identifies particular sequence variants of the PDE11A gene associated with abnormal or altered function of the gene, PDE11A as a potential novel drug target for the treatment of bilateral adrenal hyperplasia, and possibly other endocrine tumors and malignancies. CRADA Opportunity: The NICHD Heritable Disorders Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize testing for PDE11A genetic or functional defects in endocrine disease, and endocrine and other tumors or cancers. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Mammalian Cell Surface Display of Fvs for Rapid Antibody Maturation

Fri, 01 Sep 2006 06:00:00 GMT
This technology describes a new method of cell surface display of single chain antibodies for affinity maturation in a mammalian system. Cells expressing a rare mutant antibody with higher affinity were enriched about 240 fold by a single-pass cell sorting from a large excess of cells expressing wild-type antibodies with slightly lower affinity. Additionally, a highly enriched mutant with increased binding affinity for CD22 after a single selection of a combinatory library randomizing an intrinsic antibody hotspot was successfully obtained. The system is compatible with other mammalian expression systems and it is a rapid, simple and robust procedure. The method can be useful in isolating high affinity antibodies for cancer, AIDS and other diseases. CRADA Opportunity: The National Cancer Institute Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Mammalian Cell Surface Display of Fvs for Rapid Antibody Maturation. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Organic Thiophosphate Antiretroviral Agents

Fri, 01 Sep 2006 10:00:00 GMT
The current technology represents a potentially safe and effective addition to the antiretroviral drug combinations used for treatment of HIV infection. Amifostine, phosphonol and functional derivatives thereof are available for licensing and commercial development for use as antiretroviral drugs. These organic thiophosphate reducing agents inhibit HIV viral growth and protein expression in HIV-infected human white blood cells without destroying the cells. The compounds described in this technology block growth of HIV by a mechanism that is dependent on the level of aminothiol reducing agent in the cellular environment. In addition, a range of effective doses and methods for oral administration of the available organic thiophosphates is provided. CRADA Opportunity: The National Cancer Institute Laboratory of Cellular Carcinogenesis and Tumor Promotion is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these organic thiophosphate antiretroviral agents. Please contact Betty Tong, Ph.D. at 301-594-4263 or tongb@mail.nih.gov for more information.

Swine Hepatitis E Virus Available For Use in Diagnosis, Prevention and Treatment of Hepatitis E

Fri, 01 Sep 2006 14:00:00 GMT
Hepatitis E virus (HEV) is the cause of Hepatitis E, a liver disease that occurs primarily in developing countries due to fecal contaminated drinking water. Outbreaks of HEV infection have caused epidemics in Africa, Central and Southeast Asia and Mexico and cases of the disease have also been reported sporadically in more developed countries. Hepatitis E is most often overcome by a host’s natural defenses; however the disease is more severe in pregnant women, who exhibit a 20% mortality rate due to HEV infection. Presently, no vaccines or therapeutic agents, which prevent or treat HEV infection, are commercially provided.

An isolated strain of swine HEV is currently available for licensing and commercial development. The nucleotide and amino acid sequences of the available virus are significantly homologous to human HEV and antibodies induced by the agent were shown to cross react with a human HEV antigen. The present technology provides a mechanism for augmenting the immune response against HEV in infected individuals and is thus useful for the development of novel vaccines and therapeutics for prevention and treatment of HEV infection in humans. In addition, the available viral strain may be used to develop diagnostic tools for efficient detection of HEV contamination of food and water in developing countries, especially in regions of Africa, Asia and Mexico, where HEV is endemic. CRADA Opportunity: The NIAID Laboratory of Infectious Diseases, Hepatitis Viruses Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize swine HEV or its products. Please contact Robert H. Purcell at rpurcell@niaid.nih.gov for more information.

Human Protein Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) Derived Anti-Angiogenic Peptides

Fri, 01 Sep 2006 18:00:00 GMT
Cancer is the second leading cause of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. A major drawback of the existing chemotherapies is the cytotoxic side-effects that are associated with them. Thus, there is a need to develop new therapeutic approaches with reduced side-effects.

Anti-angiogenic therapy is a recent approach in cancer therapeutics targeting the formation of blood vessels that are necessary for tumor growth. Recently, the anti-angiogenic molecule bevacizumab (Avastin) has gained approval from the FDA for the first-line treatment of metastatic colon cancer in combination with standard chemotherapy.

Human protein tissue inhibitor of metalloproteinases-2 (TIMP-2) has been shown to inhibit angiogenesis in vivo independent of metalloproteinase inhibition. This technology discloses new peptide sequences derived from TIMP-2. They retain their in vivo anti-angiogenic property acting via the same mechanism as TIMP-2 and some of them have significantly higher activity than TIMP-2. Anti-angiogenic peptidomimetics based on this technology can be developed for the treatment of angiogenesis associated diseases. CRADA Opportunity: The NCI Cell and Cancer Biology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize TIMP-2 derived anti-angiogenic peptides. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel Monoclonal Antibody Microarray

Fri, 01 Sep 2006 22:00:00 GMT
Gene expression profiling at the mRNA level has proven to be a powerful and useful tool, however this approach suffers from inherent limitations: 1) the mRNA abundance does not typically correlate well with protein abundance and 2) protein structure, activity, and function can be altered and regulated by post-translational modifications. Thus, there is growing recognition that these approaches should be complemented by profiles of the gene products or proteins themselves. The present invention provides methods for constructing and using a novel Monoclonal Antibody Microarray which allows high-throughput determination of protein expression profiles from serum, tissue, and cultured cells.

The Monoclonal Antibody Microarray consists of more than 1000 different antibodies immobilized on a glass slide, which recognize antigens from several groups of proteins, including cytokines, kinases, apoptotic proteins, growth factor receptors, tumor suppressors, and oncoproteins. Protein samples to be identified and quantified are labeled with fluorescence and hybridized to the antibodies immobilized on the arrays. By differentially labeling two protein samples (dual-color labeling) and co-hybridizing to the same microarray, a direct comparative analysis of protein expression can be performed using as little as 100 ìg of total protein. This method allows a large number of samples to be screened in parallel on identical arrays. CRADA Opportunity: The NCI-Laboratory of Molecular Technology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this novel monoclonal antibody microarray. Please contact Betty Tong, Ph.D. at 301-594-4263 or tongb@mail.nih.gov for more information.

Novel Treatment of Vascular Cognitive Impairment

Sat, 02 Sep 2006 02:00:00 GMT
Available for licensing are methods and formulations for treating or preventing Vascular Cognitive Impairment (VCI) through mucosal administration of E-selectin, an inducible adhesion molecule on endothelial cells. Vascular dementia is defined as the loss of cognitive function resulting from ischemic, ischemic-hypoxic, or hemorrhagic brain lesions as a result of cerebrovascular diseases and pathologic changes. Presently no adequate medical treatment exists for VCI.

Cerebrovascular disease causes proinflammatory cytokines such as IL-1 and TNF to induce the expression of E-selectin on human endothelium. E-selectin mediates the adhesion of various leukocytes, including neutrophils, monocytes, eosinophils, natural killer cells, and a subset of T cells to the activated endothelium. Activation of vascular endothelial cells by proinflammatory cytokines is believed to be involved in conversion of the luminal surface of endothelium from anticoagulant and anti-inflammatory to procoagulant and pro-inflammatory. These vascular changes are thought to underlie the development of VCI.

Mucosally administered antigens can inhibit immune responses in an antigen specific fashion by inducing a subset of lymphocytes to produce anti-inflammatory cytokines in the presence of the antigen. This type of tolerance has been termed "bystander suppression". In an animal model of VCI, intranasal administered E-selectin suppressed activation of vessel segments beginning to express E-selectin and thus prevented the development of VCI. Immunosuppression via antigen-specific modulation of the immune response (mucosal tolerance) should have no systemic immunosuppressive effects. CRADA Opportunity: The NINDS Stroke Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of E-selectin for treatment of VCI. For more information, please contact: Laurie Arrants, NINDS Technology Transfer Office, 301-435-3112; arrantsl@ninds.nih.gov.

Differential Expression of Molecules Associated with Intra-Cerebral Hemorrhage

Fri, 01 Sep 2006 06:00:00 GMT
Stroke affects 15 million people worldwide each year, and is the number three leading cause of morbidity in the United States. Although most forms of stroke are ischemic in nature, approximately 10-15% of strokes are hemorrhagic. At present, clinical applications for distinguishing between these two forms of stroke do not exist.

The present invention describes a highly predictive, cost-effective diagnostic assay capable of detecting whether an individual has suffered from an intracerebral hemorrhagic stroke and the likelihood of neurological recovery. It comprises a rapid screening device for measuring differential expression patterns of nucleic acid molecules or proteins of at least four hemorrhagic stroke-related genes. Accurate prediction of hemorrhagic stroke will improve rapid diagnosis and aid in determining early treatment regimens. CRADA Opportunity: NINDS is also seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this assay for determining hemorrhagic stroke victims. For additional information, please contact: Heather Gunas, J.D., M.P.H; NINDS c/o NCI TTB; 6120 Executive Blvd., Suite 450, Rockville, MD 20852; Phone: 301-451-3944; Fax: 301-402-2117; Email: gunash@mail.nih.gov.

Diagnostic and Therapeutic Use of SPANX-N Genes in Cancer and Fertility

Fri, 01 Sep 2006 10:00:00 GMT
Cancer is the second leading cause of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. In spite of the success of cancer screening and early diagnosis cancer still remains a life threatening disease. There is a great need for the development of new markers and new therapeutic strategies that would more accurately predict the outcome of the disease and aid in the proper management of cancer. Antibody-based strategies have taken a lead among the new cancer therapeutic approaches.

This technology describes the identification of the link between expression of individual members of the SPANX-gene cluster and malignancies including prostate cancer. SPANX-genes consist of two subfamilies, SPANX-A/D and SPANX-N1/N5. The invention provides SPANX polypeptides, nucleic acids and antibodies that could be useful for detecting and treating prostate or other cancers. The SPANX-N genes are a family of related genes that are expressed in normal testis and in tumor cells in humans including melanoma, bladder carcinomas and myelomas. The SPANX cancer/testis antigens thus represent good candidates for diagnosis or treatment of several cancers. The present invention also describes a new approach for mutation screen of the SPANX gene cluster, including gene amplification, linking predisposition to prostate cancer with a specific architecture of the SPANX gene cluster. Additionally, due to the differential localization of SPANX-proteins in the spermatozoa, the mutational screen can be also used for diagnostics of infertility. Developed antibodies against SPANX-A/D and SPANX-N1/N5 proteins can be used for i) diagnostics of cancer, ii) diagnostics of infertility and iii) for the development of new contraceptives. CRADA Opportunity: The National Cancer Institute Laboratory of Biosystems and Cancer is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this new diagnostic marker for malignancy and infertility and new targets for immuno-cancer therapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

The Mucus Slurper: A Novel Device to Keep the Endotracheal Tube (ETT) Free of All Mucus, Without Suctioning

Tue, 01 Aug 2006 14:00:00 GMT
Available for licensing and commercial development is a mucus slurping device to remove all mucus, before mucus reaches the tip of the endotracheal tube (ETT); thus, no mucus ever enters the ETT, and the ETT remains always clean - without suctioning. A Mallinckrodt Hi-Lo® CASS (continuous aspiration of subglottic secretions) endotracheal tube is modified by appending to the distal-most tip of a cut-off CASS tube a molded, hollow, concentric plastic ring with 3 - 4 (or more) small (less than l mm in diameter) suction ports, the latter positioned in the most dependent part of the ETT (Figure 1). The CASS line was extended to the very tip of the ETT, and suction was activated for approximately 0.5 s, synchronized to the early part of expiration; and repeated once a minute, or as desired. All mucus was collected in a small in-line vial. Healthy, anesthetized and paralyzed sheep, were intubated with a modified 8 mm CASS ETT tube with attached “Mucus Slurper”; with sheep lying prone, trachea/neck oriented below horizontal. Never suctioned. At the end of the 72 h study, sheep were electively euthanized, and autopsied.

Figure 1. Normal arterial blood gases. No traces of mucus were found along the entire length of the ETT. There were no gross abnormalities of the tracheal mucosa; Bacterial cultures of the 5 lobes of the lungs were negative. The Mucus Slurper represents a new concept that may significantly contribute to improved care of patients intubated and mechanically ventilated; with no need for suctioning/cleaning, and free of ventilator associated pneumonia. CRADA Opportunity: The NHLBI Pulmonary Critical Care Medicine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the endotracheal tube mucus cleaning device and related laboratory interests. Please contact Marianne Lynch at 301-594-4094 or lynchm@nhlbi.nih.gov for more information.

Methods and Compositions for the Production of Highly Effective Vaccines Against Cancers and Infectious Diseases

Tue, 01 Aug 2006 18:00:00 GMT
Because cancers and infectious diseases remain prominent causes of death among adults and children worldwide, the availability of vaccines targeting these conditions is a global health priority. With the current vaccine development state-of-the-art, there are limitless combinations of enhancing molecules that can be used with antigen vaccines targeting these diseases. The technology offered for licensing and commercial development combines effective aspects of antigen-vaccines, including peptides and other forms of vaccination, with enhancing molecules, including co-stimulation of T cell immunity for efficient vaccine development.

The claimed invention includes a non-viral polynucleotide vector encoding immune enhancing molecules, such as the T cell co-stimulatory molecule B7.1 (CD80), which significantly enhance cellular immune responses when combined with antigen stimulation. Delivery of this co-stimulatory molecule as non-replicating DNA with any antigenic form, peptides in this case, overcomes the problems of combining enhancing molecules with the antigen in the same DNA vector, co-infecting or transfecting these molecules in the same antigen presenting or tumor cell, or manufacturing enhancing molecules in the same format as the antigens. Furthermore, the use of this chimeric vaccine with the enhancing molecule expressed as polynucleotide vector overcomes the low antigenicity and safety considerations of viral vectors, as well as the instability and conformational maintenance challenges associated with the use of full-length protein delivery. Furthermore, polynucleotide’s constructs encoding enhancing molecules are inexpensive to produce and can potentially be used along with any form of antigen vaccine delivery system, including peptides, full-length proteins and naked DNA antigens. CRADA Opportunity: The National Cancer Institute Vaccine Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize methods and compositions for the production of highly effective vaccines. Please contact John D. Hewes, Ph.D., at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of Grape Skin Extracts as Anti-Cancer Agents

Tue, 01 Aug 2006 22:00:00 GMT
The invention describes anti-tumor effects of extracts from grape skins. Grape skin extract and derivatives may therefore be useful as preventive or therapeutic agents against tumor development.

Literature indicates that grape and red wine consumption may be inversely associated with prostate cancer risk. Moreover, to date there are no known grape skin extract-associated toxicities described. The current invention discloses that grape skin extract, or purified fractions thereof, inhibited metastatic growth in human prostate transformed cell lines. Specifically, grape skin extract induced cellular apoptosis via inhibition of the phosphatidylinositol 3-kinase (PI3-K)/Akt survival pathway.

Historically, anti-tumor effects of grapes were mainly attributed to resveratrol, a phytoalexin present in grapes, nuts and wild berries. However, resveratrol’s mechanism of anti-tumor action is distinct from that of grape skin extract, in that it arrests cell cycle division without significant induction of apoptosis.

The current invention also provides for methods of treating patients with prostate cancer or persons at risk for developing prostate cancer with compositions that include grape skin extract or active anti-tumor fractions thereof. CRADA Opportunity: The NCI's Laboratory of Cell Regulation and Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Patrick Twomey, Ph.D. at 301-496-0477 or twomeyp@mail.nih.gov for more information.

ABCB1 Genotyping to Predict Paclitaxel Toxicity

Wed, 02 Aug 2006 02:00:00 GMT
Paclitaxel has been a frontline chemotherapeutic drug used for the treatment of various cancers including metastatic breast cancer and ovarian cancer. Its use has successfully prolonged patient survival. A major drawback of paclitaxel is the cytotoxic side-effects that are associated with it such as myologenic and neurogenic toxicities. The degree of such toxicities varies with individual patients. Predicting the extent of such toxicities following paclitaxel treatment will immensely help in defining optimal treatment schedules for each individual patient. Concurrently, it will significantly improve patient quality of life.

This technology describes the identification of three genetic markers in the ABCB1 (MDR-1, P-glycoprotein) gene that can be used to predict the degree of neutropenia and peripheral neuropathy that an individual will experience following paclitaxel treatment. These markers were identified using DNA from blood samples of cancer patients undergoing paclitaxel treatment. This technology can be developed into a routine blood test to identify patient subsets that are more susceptible to paclitaxel treatment associated neutropenia and neuropathy. CRADA Opportunity: The NCI Medical Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize ABCB1 genotyping to predict paclitaxel toxicity. Please contact Betty Tong, Ph.D. at 301-496-0477, tongb@mail.nih.gov for more information.

Hybrid T-Cell Receptors for the Development of Improved Vaccines

Tue, 01 Aug 2006 06:00:00 GMT
Cancer is one of the leading causes of death in United States and it is estimated that there will be more than half a million deaths caused by cancer in 2006. A major drawback of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Immuno-therapy has taken a lead among the new cancer therapeutic approaches. Adoptive immunotherapy is one of the most promising new therapeutic approaches that enhance the innate immunity of an individual to fight against a certain disease.

T cell receptors (TCR) are the proteins responsible for the T cell’s ability to recognize infected or transformed cells. TCR consists of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit the recognition signal by interacting with other proteins.

The present invention involves the construction of hybrid anti-cancer TCR that is half mouse and half human. Functional analysis reveals that human TCR with a mouse constant region is significantly better than pure human TCR. This hybrid protein when put into human T cells makes these cells much better in recognizing cancer associated proteins. The hybrid protein can be used to improve the function of a T cell providing diagnostic and therapeutic applications in cancer and infectious diseases. CRADA Opportunity: The NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize hybrid T-cell receptors for the development of improved vaccines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Diagnostic and Therapeutic Strategies for Metastatic Hepatocellular Carcinoma by Targeting Osteopontin

Tue, 01 Aug 2006 10:00:00 GMT
Cancer is one of the leading causes of death in United States and it is estimated that there will be more than half a million deaths caused by cancer in 2006. For the last decade breast and prostate cancer survival rate has significantly increased thanks to contribution of screening, early detection and novel therapeutics. This success needs to be translated to other cancers as well, where there is a need of novel diagnostic and therapeutic strategies for successful disease management.

Osteopontin (OPN) is a well known serum prognostic marker for breast cancer. This technology identifies a 10 kD residue of OPN as a potential prognostic marker and therapeutic target for metastatic hepatocellular carcinoma (HCC). Mechanistically, OPN has been shown to be a novel substrate for MMP-9 and the 10kD fragment is demonstrated to be a mediator of cell invasion and metastasis. Short synthetic peptides against OPN have been shown to block OPN mediated cell invasion, providing a novel therapeutic approach targeting OPN. Finally, polyclonal antibodies against the 10kD fragment of OPN have been developed that can be used for detection of OPN in physiological fluids of HCC patients. This technology provides a novel therapeutic and diagnostic strategy for the management of HCC patients using OPN. CRADA Opportunity: The NCI Laboratory of Human Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostic and therapeutic strategies for metastatic hepatocellular carcinoma. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Real-Time Correction of Magnetic Field Fluctuations in MRI

Tue, 01 Aug 2006 14:00:00 GMT
Available for licensing is a new MRI technique that will markedly improve the diagnostic potential of the rendered images. This is a method for applying real-time corrections to prevent image distortions caused by field variations that are due to the patient's respiratory cycle or instrument instability. These field variations reduce the B₀ homogeneity in a non-uniform and spatially-dependent manner. They may lead to a variety of image artifacts such as ghosting and blurring. This method provides a way of calculating the correct electrical currents that must be applied to a set of gradients and shims, smaller magnets that are used to make fine-tune adjustments to the magnetic field in a spatially-dependent manner. As the MRI subject breathes, changes in the B₀ field occur. During a brief training session, the amplitude of these changes as a function of chest motion is recorded in a phase map. Similarly, changes in B₀ as a function of chest motion is recorded in a phase map. Similarly, changes in B₀ as a function of current intensity is available from calibration data containing B₀ as a function of coil current. As the subject undergoes a scan, compensatory currents are applied to the x, y, or z axis of the gradients and the shims coils in order to correct for the effect of respiration on the B₀ homogeneity. The shim values can be updated every 10 to 80 milliseconds during an experiment. This method results in a substantial decrease in artifacts that can obscure the overall image quality. It can be used for virtually all types of scans and MRI instruments. CRADA Opportunity: The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Martha Lubet at 301/435-3120 or lubetm@mail.nih.gov for more information.

Target-Specific Activatable Optical Probes for In Vivo Imaging

Tue, 01 Aug 2006 18:00:00 GMT
Available for licensing and commercial development is an optical imaging method capable of detecting living cancer cells in vivo. The method increases sensitivity and reduces the background signal to extremely low levels. In contrast to conventional fluorescent imaging, the strategy activates the probe after it binds to and is internalized within cancer cells. Using antibodies, reagent-receptor systems, or cytokines to target the agent to the cancer, the agent is internalized by the normal cellular process of endocytosis which in turn, leads to molecular changes within the probe itself; fluorophores are activated only in the living targeted cells.

An activatable fluorophore is one that is normally self-quenched by attachment to a peptide backbone but which can be activated by specific proteases which degrade the peptide resulting in “de-quenching.” For example, self-quenching avidin-rhodaminex, which has affinity for lectin on cancer cells, is activated after endocytosis and degradation within the lysosome. Cellular internalization of receptor-ligand pairs with subsequent activation of fluorescence via “de-quenching” provides a generalizable and highly sensitive method of detecting cancer microfoci in vivo and has practical implications for assisting surgical and endoscopic procedures. CRADA Opportunity: The NCI Molecular Imaging Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize target specific activatable optical probes. Please contact Hisataka Kobayashi or Peter Choyke at 301-451-4220 or e-mail Dr. Choyke at pchoyke@nih.gov for more information.

Hollow Waveguide Laser Delivery System for Digital Particle Image Velocity

Tue, 01 Aug 2006 22:00:00 GMT
Available for licensing and commercial development is an all-hollow-waveguide laser delivery system used for effective digital particle image velocimetry (DPIV) illumination. The system incorporates two key optical hollow waveguide components: an uncoated funnel-shaped hollow glass taper for a direct laser-to-taper coupling and a flexible hollow core waveguide for precise high-peak-power laser delivery. The principle of operation of the uncoated hollow taper is based on grazing-incidence effect. The optical taper is used for direct lens-free launching of laser radiation including from powerful lasers into fibers and waveguides. Because of the mutual action of the direct parallel laser excitation, the mode coupling process and mode filtering effect, the hollow taper serves as a mode converter that transforms the highly multimode profile of the input laser emission into a high-quality Gaussian-shaped profile at the taper output. Moreover, because of the lower power density of the output laser beam and its high quality profile, the taper ensures higher damage threshold for the delivery waveguide in comparison to the conventional lens laser-to-fiber coupling. To improve the high-peak-power delivery capability of the proposed all-hollow-waveguide DPIV illumination system, instead of a conventional solid-core fiber link, we have used a cyclic olefin polymer (COP)-coated hollow glass waveguide which is designed to minimize the waveguide attenuation losses at a typical DPIV laser wavelength of 532-nm. This waveguide provides a significantly higher laser power delivery capability and higher damage threshold. The all-hollow-waveguide DPIV laser delivery system offers essential advanced features over conventional bulk-optics-based delivery techniques in terms of formatting thin (0.5-1.0 mm), wide (10 mm or wider) and uniform laser illumination sheet; high-peak-power laser delivery without damaging effects (>1 GW/cm2), flexibility, miniaturization, simplified alignment, immunity to external influence (including vibrations and angular laser beam drift), and safe and confined laser delivery. CRADA Opportunity: The Food and Drug Administration's Center for Devices and Radiological Health is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact the inventors at 301-827-4685 for more information.

Complement Regulatory Gene Variants as Predictive Tests for Age-related Macular Degeneration (AMD)

Wed, 02 Aug 2006 02:00:00 GMT
Age-related macular degeneration (AMD) is a complex multigenic disorder that affects the central region of the retina (macula) and is the leading cause of legal blindness in developed countries. Age, lifestyle (e.g. smoking, diet) and genetic predisposition are major risk factors for AMD and 1.75 million adults over 40 are affected by advanced AMD in the United States with a further 7 million considered to be at risk (defined by the presence of large retinal deposits or drusen, which are the hallmark of this disease). A variety of immune-associated molecules including immunoglobulins, complement components, activators and regulators, etc. are associated with drusen and evidence suggests that AMD, like other age-related diseases such as Alzheimer's disease and atherosclerosis, involves a major inflammatory component. Several disease-susceptibility genes have been identified in family studies of macular degeneration and in patient cohorts by several groups including NIH researchers and their collaborators, and variants in the factor H gene (CFH), a major inhibitor of the alternative complement pathway, have been associated with the risk for developing AMD.

NIH researchers and their collaborators have now extended this work to two other regulatory genes of this pathway, Factor B (BF) and complement component 2 (C2). These genes were screened for genetic variation in two independent cohorts comprised of ~900 AMD cases and ~400 matched controls. Haplotype analyses revealed a significant common risk haplotype (H1) and two protective haplotypes (H7 and H10). Combined analysis of the C2/BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the cases and 56% of the controls (Nature Genetics (2006) 38, 458). This suggests that these variants can be used as predictive genetic tests in combination with other potential risk factors.

Available for licensing are methods for identifying a subject at increased risk for developing AMD by determining the presence of protective genotypes at either the BF/C2 locus and at the CFH locus. Microarrays and kits are also provided. The complex and polygenic nature of AMD suggests that the protective and risk haplotypes claimed here can be of great value not only to companies targeting Macular Degeneration but perhaps more broadly to those involved in complement-mediated inflammatory disorders. CRADA Opportunity: The NCI Laboratory of Genomic Diversity is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize functional or genetic tests on complement genes and proteins. Please contact Kathleen Higinbotham at 301-846-5465 for more information.

Adoptive Immunotherapy with T Lymphocytes Engineered for Enhanced Survival

Tue, 01 Aug 2006 06:00:00 GMT
Available for licensing is a composition, comprising genetically engineered lymphocytes, transduced to express elevated levels of cytokine proteins. This technology is useful for improving cellular adoptive immunotherapies to treat a range of infectious diseases and cancers.

Adoptive immunotherapy has repeatedly been shown to be useful in the treatment of patients with metastatic melanoma. However, clinical efficacy of this treatment is limited by the short-lived survival of the transferred, autologous, antigen-specific T cells. It would be desirable to genetically modify effector cells to provide not only enhanced effector cell survival, but also desired antigen specificity, and improved function, and safety. The current technology provides a method address this desire, by genetically modifying lymphocytes using retroviral vectors.

Specifically, isolated autologous T lymphocytes can be transformed with polynucleotides encoding endogenous cytokines, for example IL-7 or IL-15. IL-15-transduced lymphocyte cultures demonstrate prolonged in vitro persistence. In addition, T cells can be transduced to express not only cytokines but also T cell receptors to confer specificity for certain antigens. Recent data showed that human T lymphocytes engineered to express a murine anti-human p53 T cell receptor can recognize tumor cell lines, as well as fresh human tumors, and are able to kill p53-expressing human tumor cells.

Also provided in the invention are methods for treating patients with transformed lymphocytes as part of adoptive immunotherapy. Applications of this technology beyond cancer include the potential use of cytokine expressing cells in treating infectious and autoimmune diseases and vaccination. CRADA Opportunity: The NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the clinical applications of T cell receptor technology. Please contact Steven A. Rosenberg, M.D., Ph.D. at 301-496-4164 for more information.

Adoptive T-Cell Transfer After Lymphodepletion Promotes Tumor Regression

Tue, 01 Aug 2006 10:00:00 GMT
Available for licensing is a method of adoptive cell transfer (ACT) immunotherapy. Since its first description, ACT is now being developed for the supportive treatment of a variety of infectious diseases and cancer.

Current ACT methods to treat cancer are based on the ex vivo selection of lymphocytes with high avidity for recognition of tumor antigens, and their activation and numerical expansion before re-infusion to the autologous tumor-bearing host. The current invention improves ACT by including a pre-treatment regimen to ensure permissive conditions in the host for in vivo proliferation of the transferred cells. Specifically, the immune system is suppressed by pre-treatment with lymphodepleting chemotherapy. Two separate clinical trials have demonstrated that using this approach, ACT can induce lasting tumor shrinkage.

Lymphodepleting chemotherapy followed by ACT resulted in tumor shrinkage of at least 50 percent in 6 out of 13 treated patients suffering from refractory melanoma. Several patients remained cancer free for more than a year after treatment. The usefulness of combined ACT and lymphodepleting therapy for cancer treatment was confirmed when this study was extended to include 35 melanoma patients. Eighteen of the 35 patients (51%) responded to the treatment, including 3 patients who experienced ongoing complete disappearance of cancer and 15 patients had tumor shrinkage of at least 50 percent with a mean duration of almost a year after treatment. In a recent clinical trial that is not yet published, using a modified protocol to treat 23 patients, a similar response rate (56%) was seen.

This approach to ACT offers a potentially significant improvement in the treatment of many types of cancer. In addition, this method might be applicable in treating other diseases such as AIDS, immunodeficiency, or other autoimmunity for which immune effector cells can impact the clinical outcome. CRADA Opportunity: The NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize ACT therapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Amyloid Beta is a Ligand for FPR Class Receptors

Tue, 01 Aug 2006 14:00:00 GMT
Alzheimer's disease is the most important dementing illness in the United States because of its high prevalence. Five to ten percent of the United States population 65 years and older are afflicted with the disease. In 1990 there were approximately 4 million individuals with Alzheimer's, and this number is expected to reach 14 million by the year 2050. It is the fourth leading cause of death for adults, resulting in more than 100,000 deaths annually. Amyloid beta has been identified as playing an important role in the neurodegeneration of Alzheimer's disease. However, the mechanism by which this occurred was unknown, but has been postulated to be either direct or indirect through an induction of inflammatory responses.

The NIH announces the identification of the 7-transmembrane, G-protein-coupled receptor, FPRL-1, in the cellular uptake and fibrillar aggregation of amyloid beta-beta (Abeta-beta) peptides. The Abeta-beta peptides use the FPRL-1 receptor to attract and activate human monocytes and mouse microglial cells (publications referenced below), and have been identified as a principal component of the amyloid plaques associated with Alzheimer’s disease. In addition, the known anti-inflammatory drug, Colchicine, has been shown to inhibit the FPRL1 activation by amyloid and the internalization of FPRL1/amyloid beta complexes. CRADA Opportunity: The National Cancer Institute, Laboratory of Molecular Immunoregulation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialized siRNA delivery development. Please contact Donna Bialozor at 301/846-5465 or bialozod@mail.nih.gov for more information.

Methods and Compositions Related to GHS-R Antagonist

Sat, 01 Jul 2006 18:00:00 GMT
This invention describes that additional functional role for D-Lys3 GHRP-6 (a known GHS-R antagonist, peptide) as a blocker of two well-known chemokine receptors, namely CCR5 and CXCR4. These receptors are major HIV co-receptors and are critical for HIV binding, fusion and entry into human T cells, monocytes, dendritic cells, and various other cells within the body. Moreover, these receptors and their ligands play a major role in inflammation and a variety of acute and chronic disease states. Overall, these two mammalian chemokine receptors are currently major drug targets for treatment of AIDS, cancer and many immunoregulatory disorders. Many identified antagonists block one or the other receptor. Since D-Lys3 GHRP-6 actually binds and blocks both these chemokines receptors at the same time hindering their activity and HIV infectivity, D-Lys3 GHRP-6 may be a good therapeutic candidate for treatment of AIDS and inflammatory diseases. CRADA Opportunity: The National Institute on Aging's Laboratory of Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Nicole D. Guyton at 301/435-3101 or darackn@mail.nih.gov for more information.

Fluorescent Imaging and Photodynamic Treatment of Tumors

Sat, 01 Jul 2006 22:00:00 GMT
Available for licensing and commercial development are methods and compositions for optically detecting tumors, in particular disseminated intraperitoneal cancers. Unlike existing detection methods using avidin and/or galactosyl serum albumin (GSA), the current invention allows tumors to be visualized in situ, with high sensitivity and without hazardous radioactive probes. The invention also provides methods of treating tumors.

The invention describes the labeling of avidin and GSA with fluorophores. The fluorescently labeled agents selectively bind to cells expressing asialoglycoprotein receptors on the surface of tumor cells, such as in tumors of the ovary, stomach, colon or pancreas. Metastatic tumor cells can then be detected endoscopically, laparoscopically, or during surgery with an appropriate imaging system.

The fluorescently labeled avidin and GSA can be used diagnostically, but also have an application for treating cancer. Using photoactivatable fluorophores linked to avidin or GSA, free radicals can be produced which results in localized death of tumor cells upon exposure to excitation with the appropriate wavelength. CRADA Opportunity: The National Cancer Institute Molecular Imaging Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tumor specific imaging agents. Please contact Laurie Zipper, Ph.D., at 301/594-4650 or zipperl@mail.nih.gov for more information.

A Newly Discovered Bacterium in the Family Acetobacteraceae

Sun, 02 Jul 2006 02:00:00 GMT
Available for licensing and commercial development is a newly discovered bacterium in the Acetobacteraceae family. This bacterium was isolated, characterized and grown from lymph nodes of a patient with chronic granulomatous disease (CGD), a rare genetic disorder that impairs the immune system.

This Gram-negative bacterium is an aerobic, facultative methylotroph that produces yellow pigmented colonies. The closest nucleic acid sequence match was to Gluconacetobacter sacchari (95.7% similarity) of the acetic acid bacteria. The newly described bacterium belongs to a new genus and species in the Acetobacteraceae family and was named Granulibacter bethesdensis. Acetobacteraceae are characterized by their ability to convert alcohol (ethanol) to acetic acid in the presence of air. Members of this family are used industrially in the production of vinegar, and are encountered during fermentation of wine.

G. bethesdensis can breakdown methanol, formaldehyde, ethanol and their intermediate breakdown products into non-toxic end-products. Examples of non-toxic end-products include carbon dioxide, water, and acetic acid.

The invention provides the complete genome sequence from the bacterium. Also included are permission to purify and utilize unique enzymes that the bacterium uses to degrade organic materials, for example methanol dehydrogenase, formaldehyde-activating enzyme, and methylenetetrahydrofolate dehydrogenase (NADP+). CRADA Opportunity: The NIAID Laboratory of Host Defenses is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Kelly Murphy at 301/451-3523 or murphykt@niaid.nih.gov for more information.

Method for Expanding Allodepleted Antigen Specific T Cells

Sat, 01 Jul 2006 06:00:00 GMT
Available for licensing and commercial development are methods of producing a population of purified non-alloreactive antigen-specific T cells that recognize an antigen of interest. Thus, the population of donor T cells can be used to produce immune response against the antigen of interest (e.g., cytomegalovirus) in a recipient without producing an immune response to the recipient. Currently available methods for isolating and expanding antigen-specific T cells can be inefficient and produce populations of cells that include donor-reactive T cells. The present method enables rapid production of populations of T cells that recognize an antigen of interest but are depleted for alloreactive T cells: A population of donor T cells is contacted with a population of irradiated recipient antigen presenting cells (T-APCs) to produce a population of alloreactive donor T cells. The alloreactive T cells are removed by purification with an antibody that specifically binds a cell surface marker (e.g., CD25, CD69, CD38 or CD71). The population of allo-depleted donor cells is then contacted with donor T antigen presenting cells (T-APCs) expressing an antigen of interest and produces a population of donor allo-depleted activated CD4 and CD8 T cells. CRADA Opportunity: The NHLBI Hematology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a Method for Expanding Allodepleted Antigen Specific T Cells. Please contact Dr. A. J. Barrett at 301/402-4170 or barrettjj@mail.nih.gov for more information.

Diamidine Inhibitors of Tdp1 as Anti-Cancer Agents

Thu, 01 Jun 2006 10:00:00 GMT
Available for licensing and commercial development are methods and compositions for treating cancer, using novel compounds derived from diamidine. Diamidine and its derivatives are potent inhibitors of tyrosyl-DNA-phosphodiesterase (Tdp1), which may be useful in chemotherapy.

Camptothecins are effective Topoisomerase I (Top1) inhibitors, and two derivatives (Topotecan® and Camptosar®) are currently approved for treatment of ovarian and colorectal cancer. Camptothecins damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3’-end of the broken DNA. Tdp1 repairs Top1-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond. Thus, the presence and activity of Tdp1 can reduce the effectiveness of camptothecins as anti-cancer agents. In addition, Tdp1 repairs free-radical-mediated DNA breaks.

Inhibition of Tdp1 using diamidine or its derivatives, may reduce repair of DNA breaks and increase the rate of apoptosis in cancer cells. In addition, diamidine derivatives have the potential to enhance the anti-neoplastic activity of Top1 inhibitors, by reducing repair of Top1-DNA lesions through inhibition of Tdp1. CRADA Opportunity: The Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Tdp1 inhibitors for the treatment of cancers. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Novel Human IGF-1 Specific IGF-I and IGF-II Cross-Reactive Human Monoclonal Antibodies as Potential Anti-tumor Agents

Thu, 01 Jun 2006 14:00:00 GMT
Cancer is one of the leading causes of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. A major drawback of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Monoclonal antibody-based therapies have taken a lead among the new cancer therapeutic approaches.

The type 1 insulin-like growth factor (IGF) receptor (IGF1R) is over-expressed by many tumors and mediates proliferation, motility, and protection from apoptosis. Agents that inhibit IGF1R expression or function can potentially block tumor growth and metastasis. Its major ligands, IGF-I, and IGF-II are over-expressed by multiple tumor types. Previous studies indicate that inhibition of IGF-I, and/or IGF-II binding to its cognizant receptor negatively modulates signal transduction through the IGF pathway and concomitant cell proliferation and growth. Therefore, use of humanized or fully human antibodies against IGFs represents a valid approach to inhibit tumor growth.

The present invention discloses the identification and characterization of three (3) novel fully human monoclonal antibodies designated m705, m706, and m708, which are specific for insulin-like growth factor (IGF)-I. Two (2) of the three (3) antibodies, m705 and m706 are specific for IGF-I and do not cross react with IGF-II and insulin while, m708 cross reacts with IGF-II. These antibodies can be used to prevent binding of IGF-I to its concomitant receptor IGFIR, consequently, modulating diseases such as cancer. Additional embodiments describe methods for treating various human diseases associated with aberrant cell growth and motility including breast, prostate, and leukemia carcinomas. Thus, these novel IGF-I antibodies may provide a therapeutic intervention for multiple carcinomas. CRADA Opportunity: The NCI Center for Cancer Research Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize monoclonal antibodies to treat human diseases. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Agonist Epitopes for Renal Cell Carcinoma

Thu, 01 Jun 2006 18:00:00 GMT
Approximately 30,000 patients are diagnosed with renal cell carcinoma (RCC) each year in the United States, and an estimated 12,000 patients die of this disease. Most patients are diagnosed with advanced local disease or metastatic disease. Metastatic RCC carries a poor prognosis with median survivals in the range of 10-12 months. Drugs that inhibit VEGF receptor tyrosine kinases such as Sorafenib and Sunitinib have recently been approved by the FDA to treat metastatic RCC. Although a significant percentage of patients will achieve a partial response or disease stabilization with these agents, complete responses are rare and disease progression eventually ensues. RCC is unusual among solid tumors as it appears to be susceptible to immunotherapy. Cytokines such as IL-2 and IFN-alpha nonspecifically stimulate the immune system resulting in disease regression. Unfortunately, these drugs achieve success in only a minority (15-20%) of the metastatic RCC patient population. Therefore, new methods are needed to improve on immune-based therapies and expand the curative potential of therapies for patients with RCC.

The present invention discloses peptides and antigen epitopes specific for RCC for use in the diagnosis, vaccination, or adoptive infusion of antigen specific T cells to treat patients with metastatic RCC. The immunogenic peptide, which binds to the HLA-A11 epitope, was identified in a patient with metastatic RCC that under went an investigational allogeneic hematopoietic stem cell transplant. Cancer regression occurred post-transplant consistent with a graft-vs-tumor effect. A T-cell line, expanded from the patient’s blood cells at the time of tumor regression, was isolated and subsequently shown to kill the patients RCC cells in vitro. Expression and sequencing studies revealed that the patient’s T-cells recognize an antigen epitope derived from a human endogenous retrovirus (HERV). Further, pre-clinical studies using quantitative real-time PCR found that this HERV was expressed in eight of 14 RCC tumor cell lines with no HERV expression in patient fibroblasts, hematopoietic cells or in c-DNAs analyzed from 48 different normal tissues. Plans are underway to investigate the immunogenic potential of this peptide to induce expansion of T-cells that are cytotoxic to RCC cells in vitro and in pre-clinical animal models. CRADA Opportunity: The Hematology Branch of the NHLBI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutic treatment approaches targeting this novel RCC antigen. Please contact Dr. Richard Childs at 301/594-8008 or childsr@nhlbi.nih.gov for more information.

Beta-Amyloid PET Imaging Agents

Thu, 01 Jun 2006 22:00:00 GMT
Available for licensing and commercial development are two novel classes of compounds useful as radioligands for in vivo imaging of beta-amyloid peptides and plaques in humans.

Beta-amyloid peptide deposition in the brain is a pathological feature of Alzheimer’s disease (AD). Early detection of beta-amyloid load in patients with suspected AD is vital to initiating early treatment, which can improve cognitive function and quality of life for many patients.

The invention describes novel derivatives of imidazopyridinylbenzeneamine (IMPY) and benzothizolylbenzeneamine (BTA), which demonstrate high in vitro binding affinity to human beta-amyloid. The difference between existing IMPY compounds and the novel derivatives is the substitution of an aryl halide with an aryl thioether group and replacement of a sulfur group of the pyridine ring with a nitrogen group. The new classes of compounds have the potential of providing improved amyloid imaging agents for Positron Emission Tomography (PET) with higher specificity for amyloid, low background noise, better entry into the brain and improved labeling efficiency.

In addition to the novel compounds, the invention also includes: 1) a new method of synthesizing the IMPY derivatives, using palladium as a catalyst, 2) methods of imaging beta-amyloid deposits in the brain by in vivo PET, magnetic resonance imaging (MRI) and other imaging methods involving the use of these compounds, and 3) and methods of labeling these compounds with radiotracers ([11-C] and [18-F]). CRADA Opportunity: The NIMH Molecular Imaging Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Beta-Amyloid PET Imaging Agents. Please contact Suzanne Winfield at winfiels@mail.nih.gov for more information.

Generation of Regulatory T Cells for Immunotherapy

Fri, 02 Jun 2006 02:00:00 GMT
Abnormalities in immunoregulation are responsible for a wide variety of disorders such as autoimmune disease, chronic inflammatory diseases, and allergic diseases. These diseases include systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, multiple sclerosis, Crohn’s disease and asthma. The defining event for induction of an immune-mediated disorder is the loss of T cell tolerance to self-antigens, which is provided by regulatory T cells. Traditional methods for treating immune-mediated disorders involve the use of steroids or other immunosuppressive drugs, which have significant undesirable side effects.

This invention provides methods for generating regulatory T cells by culturing CD4+CD25- T cells with autologous antigen-presenting cells (APCs) in the presence of the Th2 cytokines interleukin-4 (IL-4) and/or interleukin-13 (IL-13). Immunotherapy via this mechanism is anticipated to have a large number of potential therapeutic applications. Methods are also provided for treatment of autoimmune disease or inflammation in a subject by administration of an IL-4 agonist, as well as methods of treating cancer by administration of an IL-4 antagonist. CRADA Opportunity: The NIAMS, Autoimmunity Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a process for the generation of regulatory T cells for immunotherapy. Please contact Dr. Peter E Lipsky at 301/594-0596 or lipskyp@mail.nih.gov for more information.

Multiplex Microarray for Simultaneous Detection of Hepatitis C Virus, Hepatitis B Virus, and Human Immunodeficiency Virus Type-1

Thu, 01 Jun 2006 06:00:00 GMT
Available for licensing and commercial development are patent rights that cover a specific and sensitive microarray (TTD -V-1) and multiplex assay for the simultaneous detection and discrimination of Hepatitis C Virus (HCV), Hepatitis B Virus (HBV) and Human Immunodeficiency Virus Type-1 (HIV-1), which include both RNA and DNA genomes. Four specific probes (30-45 bp oligonucleotides) for each of these three viruses as well as the two internal controls were designed. Totally, each microarray consists of 20 probes immobilized on silylated glass slides. The single-stranded Cy5-labeled samples for microarray hybridization were obtained from labeling the amplicons using primer extension thermocycling. The multiplex microarray assay was able to detect and discriminate as low as 3 copies of genotypes A, B, C, D, and 10 copies of genotype E of HBV, 10 copies of HCV (genotype 1b), and 20 copies of HIV-1 (group M, subtype B) in a single multiplex reaction. The microarray assay could also detect the coexistence of two or three of these viruses and discriminate them simultaneously. The results of this study demonstrated the feasibility and performance of microarray-based multiplex detection of the three viruses, HCV, HBV, and HIV-1 in comparison with conventional individual PCR and gel electrophoresis technique. CRADA Opportunity: The Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Beatrice Droke, Technology Development Coordinator, FDA, (301) 827-7008 for more information.

Use of Tetracyclines as Anti-Cancer Agents

Thu, 01 Jun 2006 10:00:00 GMT
The invention describes compositions of tetracycline compounds and their derivatives as having anticancer activity, as well as methods of treating cancer. Tetracyclines are commonly used as antibiotics; however, testing of these compounds in a high throughput screening system revealed certain derivatives to be potent inhibitors of tyrosyl-DNA-phosphodiesterase (Tdp1).

Camptothecins are effective Topoisomerase I (Top1) inhibitors, and two derivatives (Topotecan® and Camptosar®) are currently approved for treatment of ovarian and colorectal cancer. Camptothecins damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3’-end of the broken DNA. Tdp1 repairs Top1-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond. This can reduce the effectiveness of camptothecins as anti-cancer agents. In addition, Tdp1 repairs free-radical-mediated DNA breaks.

As disclosed in the instant technology, tetracyclines have the potential to enhance the anti-neoplastic activity of Top1 inhibitors by reducing repair of Top1-DNA lesions through inhibition of Tdp1. Inhibition of Tdp1 may also reduce repair of DNA breaks and increase the rate of apoptosis in cancer cells, making them potential anti-cancer agents on their own. CRADA Opportunity: The Laboratory of Molecular Pharmacology at the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tetracycline derivatives, particularly optimizing them for therapeutic use. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Biofunctionalized Quantum Dots for Biological Imaging

Thu, 01 Jun 2006 14:00:00 GMT
Available for licensing is intellectual property covering carbohydrate-encapsulated quantum dots (QD) for use in medical imaging and methods of making the same. Certain carbohydrates, especially those included on tumor glycoproteins are known to have affinity for certain cell types. One notable glycan used in the present invention is the Thomsen-Freidenreich disaccharide (Galb1-3GalNAc) that is readily detectable in 90% of all primary human carcinomas and their metastases. These glycans can be exploited for medical imaging. Quantum Dots (QDs) are semiconductor nanocrystals (CdSe or CdTe) with detectable luminescent properties. Encapsulating luminescent QDs with target-specific glycans permits efficient imaging of the tissue to which the glycans bind with high affinity. Accurate imaging of diseased cells (e.g., primary and metastatic tumors) is of primary importance in disease management. The inventors describe a method for enhancing the luminescence of carbohydrate-encapsulated QDs by addition of specific functional units in a novel synthesis of hybrid CdTe-based core-shell semiconductor nanocrystals. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, Laboratory of Medicinal Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize carbohydrate-encapsulated quantum dots. Please contact Dr. Melissa Maderia by phone: (301) 846-5465 or fax: (301) 846-6820 or e-mail: maderiam@mail.nih.gov for more information.

Immortal Human Prostate Epithelial Cell Cultures as a Prostate Cancer Model

Thu, 01 Jun 2006 18:00:00 GMT
The National Institutes of Health has multiple immortalized, malignant, human, adult prostate epithelial cell lines available for license. They are useful as models in epithelial cell oncogenesis studies and in the diagnosis and treatment of prostate cancer.

The cell lines were generated from primary adenocarcinomas of the prostate. Long-term cultures were established by immortalizing cells with human papillomavirus (HPV) transforming proteins. The cultures were characterized and single-cell clones with unique genetic characteristics were selected based on allelic loss of heterozygosity (LOH). Tissue-matched normal cell lines are available also, useful for the appropriate controls.

The invention also encompasses polyclonal and monoclonal antibodies directed to the cell lines, which may be useful as immunotherapeutics. CRADA Opportunity: The NCI Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D., at 301-435-3121 or hewesj@mail.nih.gov,/a> for more information.

Novel Glycated Peptides and Proteins as Biomarkers for Diabetes Control

Mon, 01 May 2006 22:00:00 GMT
A primary goal of diabetes therapy is to improve control of blood glucose levels (known as glycemic control) in patients. Prospective studies of both Type 1 and Type 2 diabetes indicate that careful glycemic control significantly reduces the risk of microvascular, neurological, and cardiovascular complications of diabetes.

The current method to monitor glycemic control is by measurement of the relative concentration of glycated red-cell hemoglobin (HbA1C). However, levels of HbA1C, an intracellular protein, reflect glycemic control over a timeframe of several months. They are also susceptible to a variety of perturbing factors such as hematologic disorders, kidney disease, aspirin or penicillin use, or alcohol intake.

This technology describes a family of novel glycated peptide and protein biomarkers for glycemic control, as well as a method to monitor glycemic control in diabetic patients. In contrast to HbA1C, which is an intracellular protein, the glycated proteins described in this invention are found in blood plasma, and might reflect changes in glycemic control more rapidly, and with more sensitivity. A test developed using this technology could be envisioned to supplement or replace current monitoring of glycemic control by HbA1C. Also described are methods for making antibodies and aptamers that bind the described glycated peptides and proteins, and a database listing glycated peptide concentrations in diabetic and control samples. CRADA Opportunity: The National Institute of Environmental Health Sciences, Office of Clinical Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John S. Penta, Ph.D. at 919-541-3696 or penta@niehs.nih.gov for more information.

Sensitive Antibody-based Assay for the Measurement of c-Met Concentration Shed in Bodily Fluids Useful in the Diagnosis and Prognosis of Cancer

Tue, 02 May 2006 02:00:00 GMT
This invention described and claimed in these patent applications provide for methods and assays which may be used to diagnose and follow the progression of cancers associated with c-Met expression. The data supporting this application suggests that c-Met expression may be an appropriate biomarker in certain types of cancer. In particular, the applications describe a sensitive assay useful for monitoring levels of c-Met shed in the urine or blood. The assay was developed using commercially available reagents. The applications contain data, derived from patient samples, supporting the clinical utility of the assay. In particular, the data shows the use of the assay to detect levels of shed c-Met in patients with bladder cancer, renal cancers and prostate cancer. Data showing the applicability of the assay for glioblastoma was derived using murine models of cancer for glioblastoma. Data showing the applicability of the assay for breast cancer, melanoma and prostate cancer was derived using various human cell line model systems.

HGF/met signaling has been most widely studied in settings related to cancer. It has been demonstrated to have a role in metastasis and angiogenesis. In addition to cancer, HGF activity has also been linked, through its role in apoptosis, to Alzheimer’s disease and cardiovascular disease. CRADA Opportunity: The National Cancer Institute, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HGF/c-Met signaling as it relates to tissue repair and regeneration, cancer, and other diseases. Please contact Brian W. Bailey, Ph.D. at (301) 451-2158 or bbailey@mail.nih.gov for more information.

Adoptive Immunotherapy with Autologous Natural Killer Cells

Mon, 01 May 2006 06:00:00 GMT
Dr. Rosenberg and colleagues have clearly demonstrated that T-lymphocytes can mediate the regression of metastatic melanoma. However, not all patients with cancer are eligible for or respond to this type of immunotherapy. In some patients, the tumor infiltrating lymphocytes (TIL) do not expand sufficiently, or do not exhibit sufficient tumor specific reactivity.

Studies in mice have shown that adoptive transfer of NK cells activated in vitro can significantly reduce the load of Acute Myelogenous Leukemia (AML), and intravenously-injected autologous NK cells have been shown to significantly decrease melanoma tumor outgrowths. To this end, Dr. Rosenberg and colleagues have developed an alternative type of immunotherapy, which involves the adoptive transfer of autologous natural killer (NK) cells. This method consists of three parts: a) Isolation and expansion of NK cells ex-vivo; b) Administration of nonmyeloablative lymphodepleting chemotherapy regimen to the patient; and c) Reconstitution of the patient’s immune system by infusion of NK cells and interleukin 2. This approach also offers the possibility of treating AIDS, immunodeficiency, and autoimmune diseases for which immune cells can impact the clinical outcome. CRADA Opportunity: The NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Natural Killer (NK) cells for their clinical use as cancer treatments. Please contact Dr. Steven Rosenberg at (301) 496-4164 or sar@mail.nih.gov for more information.

Preparation of a Peptide Targeted Human RNase, RGD-Eosinophil Derived Neurotoxin (RGD-EDN) To Specifically Target Tumor Vasculature

Mon, 01 May 2006 10:00:00 GMT
Cancer is the second leading cause of death in the United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. A major drawback of the existing chemotherapies is the cytotoxic side-effects that are associated with them. Thus, there is a need to develop new therapeutic approaches with reduced side-effects. Anti-angiogenic therapy is a recent approach in cancer therapeutics targeting the formation of blood vessels that are necessary for tumor growth. Anti-angiogenic therapeutic agents are generally devoid of toxic side-effects, recently gaining attention as cancer therapeutics with tremendous promise. Recently, the anti-angiogenic molecule bevacizumab (Avastin), a monoclonal antibody against the vascular endothelial growth factor (VEGF), has gained approval from the FDA for the first-line treatment of metastatic colon cancer in combination with standard chemotherapy. This technology describes a novel anti-angiogenic method for treating cancer. The alpha(v)beta(3)-integrin is upregulated on tumor endothelial cells and can bind RGD (Arg-Gly-Asp) peptides. By tagging the RGD peptide with the normally non-cytotoxic eosinophil-derived neurotoxin (EDN), this RNase molecule can be targeted to human vascular endothelial cells where it becomes cytotoxic. These RGD-EDN molecules inhibit the adhesion of HUVEC cells in response to endothelial growth factors. These molecules have also been shown to inhibit tumor growth in mice with Kaposi's sarcoma. This technology has therapeutic potential for a broad spectrum of cancer related diseases alone, or in combination with existing therapies. CRADA Opportunity: The National Cancer Institute, Biological Testing Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Peptide Targeted Human RNases. Please contact Bjarne Gabrielsen at (301) 846-5465 or bjg@nih.gov for more information.

T-cell Receptor Recognizing Renal Cell Carcinoma

Mon, 01 May 2006 14:00:00 GMT
Renal cell carcinoma (RCC) is the most common renal tumor with approximately 30,000 cases per year in the USA. The survival rate for this cancer is very low, where only 10% of patients survive because this carcinoma is resistant to most chemotherapies.

This technology describes a T cell receptor that was cloned from a human immune cell. This T-cell receptor recognizes a number of human kidney tumors and is not limited to use in patients with specific MHC types. This cell was able to kill other kidney cancer cells in other patients, and when this T-cell was introduced into other human immune cells, these cells also acquired the ability to kill kidney cancer cells. This invention also describes novel methods using dendritic cells to generate both CD4+ and CD8+ RCC- reactive T cells for use in antigen identification and therapeutic protocols. This is the first and only cloned T-cell receptor that recognizes a majority of human kidney tumors. CRADA Opportunity: The NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize T cell receptors and their clinical use as cancer treatments. Please contact Dr. Steven Rosenberg at (301) 496-4164 or sar@mail.nih.gov for more information.

Identification of a Novel Folliculin Interacting Protein, FNIP-1

Mon, 01 May 2006 18:00:00 GMT
Renal cell carcinoma is an important health problem in the United States, affecting 32,000 individuals each year and resulting in 12,000 deaths annually. Several familial cancer disorders with a renal epithelial tumor phenotype have been well characterized and the causative genes have been identified including the Birt-Hogg-Dube (BHD) gene. The BHD gene encodes a protein called folliculin. Mutations in BHD lead to the development of Birt-Hogg Dube syndrome, a dermatologic disorder associated with an increased risk for developing renal cancer, spontaneous pneumothorax and lung cysts.

This invention describes the cloning and characterization of the first folliculin interacting protein FNIP-1 and purified antibodies that selectively bind to an epitope of FNIP-1. FNIP-1 interacts with subunits of AMP-dependent protein kinase (AMPK). The FNIP-1/AMPK interaction places FNIP-1 and folliculin as potential interactors in cellular pathways essential for regulating cell growth and cell size. FNIP-1 may play an important role in folliculin's function. Identification of the FNIP-1 cDNA sequence will enable evaluation of sporadic renal tumors, enable the development of cancer diagnostics and aid in the treatment of BHD skin lesions. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize folliculin interacting protein FNIP-1 and purified antibodies. Please contact Kathy Higinbotham at 301-846-5465 or higinbok@mail.nih.gov for more information.

Insect Cell Production of Recombinant Adeno-Associated Virus that Produce Cytotoxic Gene Products and Applications for Solid Tumor Therapy

Mon, 01 May 2006 22:00:00 GMT
Cancer is the second leading cause of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. Due to the high incidence of death from cancer despite the use of current therapies, there is a strong need for targeted therapeutic approaches such as gene therapy.

This technology describes a new method for targeting solid tumors using gene therapy. More specifically, mammalian HEC-1 has a critical role in chromosome segregation and thus cell division. This technology involves targeted depletion of HEC-1 using shRNA against the HEC-1 mRNA inhibiting cancer cell growth in cell culture models (in vitro) as well as regressed tumor size in mouse model (in vivo). Additionally, this is the sole technology using an insect cell based recombinant adeno-associated virus (rAAV) gene transfer vehicle with high titer containing the shRNA of interest thus enabling high dosing during therapeutic intervention if necessary. This technology platform has the potential to treat a broad spectrum of cancers and related diseases. CRADA Opportunity: The National Heart, Lung, and Blood Institute, Laboratory of Biochemical Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop therapeutics using rAAV-shRNA to induce selective cytotoxicity in primary and metastatic solid tumors. Partners are sought for conducting translational research from preclinical trials to clinical trials. Please contact Dr. Vincent Kolesnitchenko, Office of Technology Transfer and Development, NHLBI at 301-594-4115 or by e-mail (vk5q@nih.gov) for more information.

Use of Cripto-1 as a Biomarker for Neurodegenerative Disease and Method of Inhibiting Progression Thereof

Tue, 02 May 2006 02:00:00 GMT
Cripto-1 is a gene that is currently thought to play an important role in several cancers, and is being developed in clinical trials as a cancer therapeutic. Presented in this invention is another use of Cripto-1 as a biomarker and possible therapeutic target for a variety of neurodegenerative diseases, including NeuroAIDS, Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and encephalitis. Cripto-1 and concomitant protein expression appears to be overexpressed by 20-fold or more in the brains of macaque monkeys and humans afflicted with NeuroAIDS. This expression is confined to neurons related to neurodegeneration. Inhibition of Cripto-1 may be associated with inhibiting the progression of these diseases via a disclosed method for inhibiting the expression or downstream signaling pathways mediated by Cripto-1. This inhibition can be achieved through the expression of various inhibitory oligonucleotides. Additionally, the development of antibodies against Cripto-1 has already been achieved for the detection of Cripto-1 in human pathological specimens.

It is estimated that by 2050, 14 million Americans will suffer from AD, representing national annual costs for caring and due to productivity lost of approximately $160 billion. Despite active research in this area, there remains urgent need to identify differentially expressed genes in and to develop methods for detecting neurodegenerative disease through assaying expression levels of specific genes. Currently, there are no drugs directed at inhibiting Cripto-1 as a therapeutic agent for AD or other neurodegenerative diseases. This invention holds the promise of market opportunities through pursuing development of Cripto-1 as a biomarker for diagnosis of and possible target for therapeutic intervention of these diseases. CRADA Opportunity: The National Cancer Institute, Mammary Biology and Tumorigenesis Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-1569 or hewesj@mail.nih.gov for more information.

Methods and Compositions for the Inhibition of HIV-1 Replication

Mon, 01 May 2006 06:00:00 GMT
This invention relates to methods and compositions for the attenuation of HIV-1 replication in human cells, and especially in CD4+ human peripheral blood mononuclear cells, such as blood monocyte-derived macrophages by targeting a host cell protein.

HIV-1 infected macrophages typically resist cell death, support viral replication, and facilitate HIV-1 transmission. We found that the gene encoding cyclin-dependent kinase inhibitor 1A (CDKN1A) is consistently expressed following virus binding, and re-expressed at the peak of HIV-1 replication. The protein encoded by this gene, also known as p21, is associated with cell cycle regulation, anti-apoptotic response and cell differentiation. Increased levels of p21 may enhance survival and long-term persistence of HIV-1 infected macrophages.

Following identification of p21 as a candidate molecule in facilitating viral replication, efforts to curtail its role were investigated as a mode of blunting infection in macrophages. RNA interference (siRNA) represents a tool to regulate gene expression and when siRNA specific for p21 or p21-specific oligonucleotides were transfected into primary macrophages to silence the expression of p21, HIV infection was aborted, thereby validating p21 as a cellular factor essential to productive HIV infection in this population.

Extending these observations, a pharmacologic agent known to influence p21 expression, the synthetic triterpenoid and peroxisome proliferator-activated receptor gamma (PPARg ) ligand, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) or its derivative di-CDDO, was shown to moderate virally-induced p21 expression and concurrently dampen HIV infection. CDDO is part of a class of synthetic triterpenoids based on natural products resembling steroids in their biogenesis and in their pleiotropic actions. A newly developed CDDO derivative, which is orally bioavailable, also suppresses HIV.

These results, coupled with the evidence that macrophage p21 is a requisite macrophage facilitator of viral replication, intensify the interest to further develop these compounds as antiretroviral agents. The anti-retroviral effect of CDDO was evident when peripheral blood mononuclear cells (PBMC) were infected with a T-tropic (X4) or dual tropic viral (R5X4) strain of HIV-1. These studies suggest that these triterpenoids may aid in the control of retroviral replication. Neither p21 oligonucleotides nor CDDO were toxic to the cultured macrophages or peripheral blood mononuclear cells. Thus, p21 inhibitors could be safe and effective anti-HIV therapeutic candidates to be used independently and/or in conjunction with current anti-retroviral therapy.

In this regard, CDDO will be entered into human trials for the first time in the near future for its anti-cancer indications, thereby determining its maximally tolerated dose for use in subsequent HIV/AIDS clinical trials. Current anti-retroviral therapy, often characterized by high toxicity and the emergence of drug resistant virus strains, may be augmented through the identification of these and other new anti-viral agents targeting host cellular molecules less prone to mutational events. CRADA Opportunity: The National Institute of Dental and Craniofacial Research, Oral Infection and Immunity Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact David W. Bradley, Ph.D., at bradleyda@nidcr.nih.gov or by phone at 301/402-0540 for more information.

Methods for Inhibiting HIV and Other Viral Infections by Modulating Ceramide Metabolism

Mon, 01 May 2006 10:00:00 GMT
This invention provides methods of inhibiting or preventing HIV-1 infections by inducing either the de novo biosynthesis of ceramide, or by activating enzymes (e.g., sphingomyelinase) involved in the generation of ceramide at the plasma membrane, or by direct incorporation of exogenous ceramide into target cell membranes. The invention describes methods for administration a retinamide compound particularly an N-(aryl) retinamide compound such as N-(4-hydroxyphenyl) retinamide (4-HPR) resulting in increased plasma membrane ceramide levels, which results in the inhibition of HIV-1 infection in monocyte/macrophages by perturbing membrane organization. In addition, because of its low toxicity in non-tumor cells, 4-HPR and related compounds are particularly suitable for long-term preventative or therapeutic administration to subjects suffering from an HIV infection or who are at risk of contracting an HIV infection. Thus, this invention provides a novel means of treating or inhibiting HIV and other viral infections by administering a retinamide compound to a patient suffering from or susceptible to such a viral infection. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research Nanobiology Program, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the clinical potential of sphingolipid-based antiviral therapies. Please contact Melissa Maderia at maderiam@mail.nih.gov or by phone at 301/846-5465 for more information.

Novel Bis-Acridones As Anti-Tumor Agents: Potential For Treating Drug Resistant Tumors

Mon, 01 May 2006 14:00:00 GMT
Cancer is the second leading cause of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006. Current chemotherapies are mostly based on the use of small molecules. A major drawback of these existing chemotherapies is the acquired or inherent resistance of certain tumors against these drugs. Treating resistant tumors has been a major challenge in the successful management of cancer, necessitating the development of new therapies to treat resistant tumors and thus expanding the life expectancy of cancer patients.

The present invention discloses novel derivatives of Bis-acridones and related molecules and their pharmaceutically acceptable salts and their use as anti-tumor agents. Some of the derivatives have high anti-tumor activity both in vitro and in vivo. In addition to its anti-tumor activity these above mentioned compounds have been shown to be potent irreversible inhibitors of P-glycoprotein, a member of the ABC transporter protein family that has a major role in conferring multi-drug resistance. Therefore, these compounds have the potential of being used in combination with traditional chemotherapy to treat drug resistant tumors. In addition, to its anti-neoplastic property some of the derivatives of this family of compounds have been shown to have anti-HIV property. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize certain derivatives of Bis-acridones and related molecules as well as their pharmaceutically acceptable salts as anti-tumor agents. Please contact Kathy Higinbotham at 301/846-5465 or higinbok@mail.nih.gov for more information.

Nanoprobes for Detection or Modification of Molecules

Sat, 01 Apr 2006 18:00:00 GMT
This invention describes "Rod-tether Nanoprobes", devices consisting of a rigid molecular rod with a flexible molecular tether attached at both ends that can detect and/or modify molecules. Each tether tip has a functional group, such as an antibody or oligonucleotide that recognizes a target molecule. In addition, one tip carries a donor fluorophore and the other carries an acceptor fluorophore. The fluorophores form a pair for Forster Resonance Energy Transfer (FRET). In the absence of the target molecule, the rod keeps the tether arms apart, while in the presence of the target molecule, both recognizers bind to the target. This binding holds the donor and acceptor fluorophores close together, allowing a FRET signal. By reducing an ELISA-like assay entirely to the molecular level, complex macroscopic or microfluidic washing and pumping systems can be eliminated. Rod-tether Nanoprobes can detect a wide variety of clinical and biowarfare reagents. The nanoprobes can also rapidly and simply detect, modify, and/or destroy endogenous molecules (e.g., proteins, mRNA) involved in a broad range of diseases. The simplest ssDNA-detecting nanoprobe has been created. CRADA Opportunity: The National Cancer Institute, Gene Regulation and Chromosome Biology Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Rod-Tether Nanoprobes. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

The Medusa™ Sequencer: A DNA or RNA Sequencing Machine the Size of a Molecule

Sat, 01 Apr 2006 22:00:00 GMT
Current high-throughput DNA sequencing methods suffer from several limitations. Many methods require multiple fluid handling steps, fixing of molecules on beads or a 2D surface, and provide very short read-lengths. The NIH inventors offer a DNA or RNA sequencing device that drastically simplifies the process by combining all elements for sequence detection in a single molecule, the Medusa™ Sequencer.

The Medusa™ Sequencer utilizes Forster Resonance Energy Transfer (FRET) to read a polynucleotide sequence while synthesizing a complementary strand. The device consists of a DNA (or RNA) polymerase labeled with a FRET donor fluorophore and attached to a set of four flexible arms. The tip of each arm carries a distinct set including one nonhydrolyzable nucleotide and one FRET acceptor fluorophore. While a Medusa™ Sequencer synthesizes a complementary polynucleotide strand, the four different arms continuously "test" the polymerase pocket creating a characteristic FRET signal for the correct nucleotide. The series of FRET signals reveals the unknown polynucleotide sequence. CRADA Opportunity: The National Cancer Institute, Gene Regulation and Chromosome Biology Laboratory, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the Medusa™ Sequencer. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

Treatment of Pulmonary Hypertension (PH) Using Nitrite Therapy

Thu, 02 Mar 2006 03:00:00 GMT
Pulmonary Hypertension (PH) occurs as a primary or idiopathic disease as well as secondary to a number of pulmonary and systemic diseases, such as neonatal PH and sickle cell disease. There is no cure for pulmonary hypertension, a nitric-oxide deficient state characterized by pulmonary vasoconstriction and systemic hypoxemia and therapies vary in efficacy and cost. Recent studies by NIH researchers and their collaborators provided evidence that the blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins [Nature Medicine 2003 9: 1498-1505]. These initial results indicate that sodium nitrite can be used as a potential cost-effective platform therapy for a wide variety of disease indications characterized broadly by constricted blood flow or hypoxia.

These results have been further corroborated by more recent work in the neonatal lamb model for PH. Inhaled sodium nitrite delivered by aerosol to newborn lambs with hypoxic pulmonary hypertension elicited a rapid and sustained reduction (65%) in hypoxia-induced pulmonary hypertension. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, short term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. [Nature Medicine 2004 10: 1122-1127]. This new, simple and cost-effective potential therapy for neonatal PH is available for licensing.

Also available for licensing are claims directed to nitrite salt formulations associated with elevated blood pressure, decreased blood flow or hemolytic disease (HHS Ref. No. E-254-2003/2) as well as for the treatment of specific conditions including hepatic, cardiac or brain ischemia-reperfusion injury and other cardiovascular conditions [J. Clin. Invest. (2005) 115:1232-1240; JAMA (2005) 293: 1477-1484] (HHS Ref. No. E-254-2003/3). CRADA Opportunity: The National Heart, Lung, and Blood Institute, Vascular Medicine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a treatment of pulmonary hypertension (PH) using nitrite therapy. Please contact Dr. Mark Gladwin by phone at 301-435-2310 or by email at mgladwin@nih.gov for more information.

Modified Growth Hormone

Wed, 01 Mar 2006 08:00:00 GMT
This invention described and claimed in this patent application provides for an improved method for producing human growth hormone (hGH) in vitro or in vivo. In particular, the patent application describes compositions and methods which are based on a modified form of human growth hormone where the regulated secretory pathway (RSP) sorting signal has been modified to provide for the constitutive secretion of human growth hormone via the nonregulated secretory pathway (NRSP) in a mammalian cell. One particular modified hGH composition, has been demonstrated to be biologically active and able to be secreted into the bloodstream in an animal model providing proof-of-concept. This invention can be applied to a non-invasive method of gene therapy to achieve sustained delivery of this therapeutic protein. CRADA Opportunity: The NICHD Office of the Scientific Director is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the non-invasive method of production and systemic delivery of growth hormone or other proteins for therapeutic purposes. Please contact Dr. Y. Peng Loh at 301/496-3239 or lohp@mail.nih.gov for more information.

Method to Disrupt Protein-Protein Interactions and its Use to Identify Compounds Able to Inhibit HIV-1 Rev Protein Multimerization

Tue, 01 Nov 2005 12:00:00 GMT
The invention provides a FRET-based assay for the study of Rev-Rev interaction in vitro, based on YFP and CFP expression constructs for Rev. Using this assay, Rev-derived small peptides that can inhibit Rev-Rev interactions and disrupt dimerization were discovered. This assay can be used as an in vitro assay for studying protein-protein interactions in general, and for the discovery of inhibitors or agonists of such interactions as potential drugs against HIV infections, as well as for the discovery of Rev dimerization inhibitors. Thus this assay can be useful for drug screening. CRADA Opportunity: In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Sensitizing Cancer Cells to DNA Targeted Therapies

Thu, 01 Sep 2005 16:00:00 GMT
Chk2 is a protein kinase activated in response to DNA double strand breaks. In normal tissues, Chk2 phosphorylates and thereby activates substrates that induce programmed cell death, or apoptosis, via interactions with p53, E2F1, PML proteins. In cancer tissues, where apoptosis is suppressed, Chk2 phosphorylates and inactivates cell cycle checkpoints (via interactions with Cdc25, phosphatases and Brca1 proteins), which allows cancer cells to repair and tolerate DNA damage. Hence, Chk2 inhibitors would be expected to protect normal tissues by reducing apoptosis, and to sensitize cancer cells to DNA-targeted agents. CRADA Opportunity: The National Cancer Institute, Laboratory of Molecular Pharmacology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Recombinant Vaccinia Viruses Expressing IL-15 and Methods of Using the Same

Thu, 01 Sep 2005 20:00:00 GMT
Vaccinia-based vaccines have a proven record of being effective vaccines in humans as well as in animals. However, accumulating evidence reveals the need for technology to improve the immune responses such vaccines generate.

The present invention discloses recombinant vaccinia viruses capable of expressing interleukin 15 (IL-15), and methods for modulating immune responses using such viruses. This invention shows that by inserting the human IL-15 gene into the vaccinia genome, more effective vaccines can be generated against infectious agents and cancer. Currently, IL-2 has been approved by the FDA for use in the treatment of patients with metastatic renal cell carcinoma or with metastatic melanoma. It has been used as a component of cancer vaccines and in various approaches for the treatment of AIDS. However, administration of IL-2 is associated with activation-induced cell death (AICD), and may lead to death of T-cells that recognize the antigens expressed in the tumor cells. Thus, IL-15 may be a superior agent in the treatment of cancer, or as a component of a vaccine directed towards cancer or infectious agents. Co-expression of IL-15 with antigens during the immunization process, according to the current invention, leads to induction of CD8+ memory T cells with higher avidity that proliferate more effectively in vivo and persist much longer in the immunized individual in addition to enhancing the levels and persistence of antigen specific antibodies thus providing substantially longer lasting cellular and humoral immunity.

This invention has the potential to be used in a variety of ways, including: (i) an improved, more efficacious vaccine candidate for smallpox, (ii) for incorporation into existing vaccinia based vaccines to enhance and confer superior long lasting immune response to viral and cancer antigens, or (iii) as a valuable source material for IL-15 production, especially should IL-15 be proven as an alternate of more efficacious cytokine than IL-2. CRADA Opportunity: In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Variable Curve Catheter

Tue, 02 Aug 2005 00:00:00 GMT
The invention provides a deflectable tip guiding device, such as a catheter, that enables the operator to vary the radius of curvature of the tip of the catheter. This is a novel variation on the classic "fixed fulcrum" tip deflectors used in minimally invasive procedures in open surgical treatments. The described device permits a more comprehensive ability to navigate complex geometric pathways in patient's body and enables better access to target structures (e.g., to all endomyocardial walls from a transaortic approach). The guiding device can be made compatible with imaging methods like MRI. The described technology can be used as a platform for a variety of interventional devices for delivery of drugs, cells, energy, or sutures through complex trajectories of the body. CRADA Opportunity: The NHLBI Translational Medicine Branch Cardiovascular Intervention Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize technology for image-guided cardiovascular interventions. Please contact Peg Koelble at koelblep@nhlbi.nih.gov for more information.

Immunogenic Peptides (Vaccines) for the Treatment of Prostate and Breast Cancer

Sat, 01 Jan 2005 05:00:00 GMT
Collectively, cancer is the second leading cause of death in the United States. Current treatments of cancer often involve non-specific strategies (such as chemotherapy) which attack healthy cells as well as diseased cells, leading to harmful side-effects. As a result, the development of more targeted means of treating cancer are highly sought. One option for a targeted treatment is the creation of a vaccine that induces an immune response only against cancer cells. In this sense, vaccination involves the introduction of a peptide into a patient that causes the formation of T cells that recognize the peptide. If those recognize a peptide found in a protein found selectively on cancer cells, those T cells can trigger the death of those cancer cells without harming non-cancer cells. This can result in fewer side effects for the patient. TARP (T cell receptor gamma alternate reading frame protein) is a protein that is selectively expressed on the cells of certain types of prostate and breast cancer. This invention concerns the identification of immunogenic peptides within TARP, and their use to create an anti-cancer immune response in patients. By introducing these peptides into a patient, an immune response against these cancer cells can be initiated by the peptides, resulting in treatment of the cancer. A phase I clinical trial in stage D0 prostate cancer patients is nearing completion. Initial results indicate a statistically significant decrease in the slope of PSA for 48 weeks after vaccination. CRADA Opportunity: The National Cancer Institute, Vaccine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize a prostate cancer vaccine targeting the TARP antigen currently completing phase I clinical trials. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov. Click here to view the NCI collaborative opportunity announcement.

New Derivative of Dextromethorphan for Use in Neuronal Therapy

Sun, 01 Aug 2004 09:00:00 GMT
This invention describes a derivative of dextromethorphan, which is a non-competitive inhibitor of the nicotinic acetylcholine receptor. Dextromethorphan is an antitussive drug used as one of the active ingredients to prevent coughs in many over-the-counter cold and cough medicines. It has also found other uses in medicine, ranging from pain relief to psychological applications. The disclosed compound may display attractive properties compared to the closely related dextromethorphan or other drugs currently in use as non-competitive inhibitors of the nicotinic acetylcholine receptors, including extended receptor inhibition and reduced side effects.

The nicotine acetylcholine receptor is a ligand gated ion channel. These receptors specifically control rapid permeation of cations through the postsynaptic cell membrane, and are key targets in drug discovery for a number of diseases such as Alzheimer's and Parkinson's disease. This superfamily of receptor proteins is separated into the nicotinic receptor superfamily (muscular and neuronal nicotinic), the excitatory amino acid superfamily, and the ATP purinergic ligand gated ion channels, and they differ only in the number of transmembrane domains found in each subunit. This newly discovered derivative of dextromethorphan may have potential therapeutic use for several conditions involving these nicotinic acetylcholine receptors. CRADA Opportunity: The National Institute on Aging, Laboratory of Clinical Investigation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a series of noncompetitive inhibitors of neuronal nicotinic acetylcholine receptors based upon the dextromethorphan and levomethorphan scaffolds including molecular modeling and synthesis of new derivatives, receptor binding and occupancy studies and non-competitive inhibition of nicotinic acetylcholine receptors subtypes and related ligand gated ion channels. Please contact Nicole Darack, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information.

Methods for Inhibiting Proinflammatory Cytokine Expression Using Ghrelin

Tue, 01 Jun 2004 13:00:00 GMT
Ghrelin, an endogenous ligand for growth hormone secretagogue receptors (GHS-R), is primarily produced by the stomach but also by many other organs systems in the body (including the immune system) serves as a potent circulating orexigen controlling energy expenditure, adiposity and GH secretion. We have discovered that ghrelin exerts anti-inflammatory effects via inhibiting the secretion of both acute and chronic cytokines including IL-1, IL-6, TNF-alpha, IFN-gamma, IL-12 p40, Il-17, various chemokines and CSFs in vitro in human and murine cells as well as in vivo in murine models of sepsis, inflammation and aging. We also found that ghrelin directly controls human growth hormone and insulin growth factor expression by human immune cells. CRADA Opportunity: The National Institute on Aging is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Methods of Inhibiting Proinflammatory Cytokine Expression Using Ghrelin. Please contact Nikki Guyton at 301-435-3101 or guytonn@mail.nih.gov for more information.

Vaccines Comprising Sand Fly Salivary Proteins for Control of Leishmania Infection

Sat, 01 Nov 2003 17:00:00 GMT
This invention relates to the use of several peptides from the salivary glands of various sand fly species for the control of leishmania infection. Many of these peptides were shown to be effective in eliciting potent immune responses in animal models and are excellent candidates for the development of vaccines against the disease. A vaccine comprising one of the peptides was used to protect mice challenged with parasites and salivary gland homogenates. A DNA vaccine containing the cDNA for this same peptide also provided protection that lasted at least 3 months after immunization and produced both intense humoral and delayed-type hypersensitivity reactions. Other experiments have shown that B cell-deficient mice immunized with the plasmid vaccine also successfully controlled leishmania infection. Current in-vivo studies continue to explore the use of these sand fly salivary peptides for use as animal vaccines.

Leishmania parasites are transmitted to their vertebrate hosts by infected sand fly bites. Sand fly saliva helps to enhance infection but immunity to the saliva protects against the infection, allowing the possibility of vaccine development. A number of major salivary proteins from sand fly species such as Lutzomyia longipalpis, Phlebotomus ariasi, and Phlebotomus perniciosus are claimed in the invention.

Leishmania infection affects as many as 12 million people worldwide, with 1.5-2 million new cases each year. Control of this disease will be a major milestone for public health efforts in endemic areas of the world. The current invention provides a potential means to achieve widespread vaccination that may lead to significantly control of the disease in areas such as South America, South Asia, and the Mediterranean where it is still a significant health problem. An effective veterinary vaccine will be of benefit to veterinary medicine and may pave the way for human vaccines against Leishmaniasis. The vaccination of animals may also have a positive impact on the epidemiology of the disease by reducing the number of animal reservoirs and the possibility of human infection. CRADA Opportunity: The NIAID OTD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "Vaccines Comprising Sand Fly Salivary Proteins for Control of Leishmania Infection." Please contact Dana Hsu at 301-451-3521 for more information.

Isolation of Hybridomas Producing Monoclonal Antibodies (MAbs) Inhibitory to Human CYP2J2

Sat, 01 Nov 2003 21:00:00 GMT
The National Institutes of Health announces three specific monoclonal antibodies that strongly inhibit and/or immunoblot the human cytochrome P450 2J2 (CYP2J2).

Cytochrome P450s catalyze the NADPH-dependent oxidation of arachidonic acid to various eicosanoids found in several species. The eicosanoids are biosynthesized in numerous tissues including pancreas, intestine, kidney, heart and lung where they are involved in many different biological activities.

MAb 6-5-20-8 selectively inhibits CYP2J2-mediated arachidonic acid metabolism by more than 80% and also immunoblots the enzyme. MAb 6-2-16-1 also selectively inhibits arachidonic acid metabolism by more than 80% but does not immunoblot the enzyme. MAb 5-3-2-2 is not inhibitory but selectively immunoblots the enzyme. These antibodies can be used to identify and quantify inter-individual variation in physiological functions and to study pharmacological drug metabolism in various tissues. CRADA Opportunity: The NIEHS is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this antibody. For collaboration opportunities, please contact Elizabeth Denholm at denholme@niehs.nih.gov.

Mucosal Cytotoxic T Lymphocyte Responses

Sun, 02 Nov 2003 01:00:00 GMT
The invention offered for licensing provides methods and compositions for induction of an antigen-specific, mucosal cytotoxic T lymphocyte (CTL) response useful in preventing and treating infections with pathogens that gain entry via a mucosal surface. The methods of the invention involve administering either a soluble antigen itself, or a polynucleotide encoding the soluble antigen, to a mucosal surface. The soluble antigens can be full length, naturally occurring polypeptides or fragments (i.e. peptides) derived from them. The soluble antigen is administered with an adjuvant at the mucosal site or without an adjuvant. Adjuvants can be, for example, Cholera toxin (CT), mutant CT (MCT), E. coli heat labile enterotoxin (LT) and others. Cytokines like IL-12 or IFNgamma can also be administered to enhance the immunoreactivity. Mucosal routes of administration include intrarectal (IR), intranasal (IN), intragastric (IG), intravaginal (IVG) or intratratracheal (IT). Soluble antigens can be derived from pathogenic viruses (e.g. HIV, influenza, or hepatitis virus), bacteria (e.g. Listeria monocytogenes), or prozoans. Furthermore, the soluble antigen can be tumor-associated antigen for cancer applications.

The utility of the technology has been extensively demonstrated when applied to HIV. Details about the HIV studies are provided in the eight (8) publications cited below. CRADA Opportunity: The Center for Cancer Research, Vaccine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Mucosal Cytotoxic T Lymphocyte Responses. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

A Novel Chimeric Bifunctional Protein for Prevention and Treatment of HIV Infection

Sat, 01 Nov 2003 05:00:00 GMT
This invention relates to bifunctional fusion proteins effective in HIV neutralization. Specifically, the invention is a genetically engineered chimeric protein composed of a soluble extracellular region of human CD4 (sCD4) attached via a flexible polypeptide linker to a single-chain construct of a human monoclonal antibody directed against a CD4-induced, highly conserved gp120 determinant involved in co-receptor interaction and virus entry. Mechanistically, the binding of the sCD4 moiety to the HIV gp120 Env glycoprotein induces a conformational change that enables the antibody moiety to bind, thereby blocking Env function and virus entry. This novel design provides the protein with unique characteristics that enables its extremely strong binding to gp120, thus rendering it a potential effective antiviral agent against HIV. Recent studies (Lagenaur et al. Retrovirology 7:11, 2010) indicate that this novel bispecific protein displays extremely broad neutralizing activity against genetically diverse primary HIV-1 isolates, with breadth much greater than previously described (Dey et al. J. Virology 77:2859, 2003). The potency is generally at least 10-fold greater than the best described HIV-1 neutralizing monoclonal antibodies, and the protein is highly active against many HIV-1 isolates that are refractory to neutralization by these antibodies. The bifunctional protein is comparably potent against isogenic virions produced from a human cell line versus PBMC; by contrast, the broadly-reactive monoclonal antibodies are much less potent against virions produced from PBMC, perhaps due to differences in glycosylation. Importantly, the bifunctional protein is composed of almost entirely human sequences. It potentially can be linked to other functional moieties to achieve desired properties (longer plasma half-life, selective killing of HIV-infected cells, imaging of viral reservoirs, etc.).

The chimeric protein of this invention has considerable potential for prevention of HIV-1 infection, both as a topical microbicide and as a systemic agent to protect during and after acute exposure (e.g. vertical transmission, post exposure prophylaxis). It also has potential utility for treatment of chronic infection, including gene therapy strategies involving hematopoietic stem cells and/or viral vectors. Such proteins, nucleic acid molecules encoding them, and their production and use in preventing or treating viral infections are claimed in the patents issued for this invention. CRADA Opportunity: The NIAID, Office of Technology Development, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "A Novel Chimeric Bufunctional Protein for Prevention and Treatment of HIV Infection." Please contact Rick Williams at 301-402-0960 for more information.

Imidazoacridones with Anti-Tumor Activity

Sun, 01 Jun 2003 09:00:00 GMT
The present invention relates to novel bifunctional molecules with potent and selective activity against colon, liver and pancreatic tumors. Compounds have low animal toxicity, excellent PK/PD characteristics and proved to be very effective in several preclinical animal models of cancer. Extensive mechanistic studies have demonstrated that compounds inhibit tumor growth through a novel mechanism. These agents are composed of an imidazoacridone moiety linked by a nitrogen containing aliphatic chain of various length and rigidity to another aromatic ring system capable of intercalation to DNA.

Previous studies on related symmetrical bis-imidazoacridones revealed that only one planar imidazoacridone moiety intercalates into DNA. The second aromatic moiety, which is crucial for biological activity, along with the linker resides in DNA minor groove, and is believed to interact with DNA-binding proteins (most likely, transcription factors and /or repair proteins). The symmetrical bis-imidazoacridones arrest the growth of sensitive cancers (especially colon cancers) but do not kill the tumors. It was hypothesized that the growth arrest was due to the inability of the affected tumor cells to repair DNA damage caused by the compounds. Remarkably, bis-imidazoacridones are very well tolerated, are very tissue selective and do not appear to damage normal tissues.

Since the binding of the symmetrical bis-imidazoacridones to DNA was unsymmetrical, the inventors have developed unsymmetrical compounds in which one imidazoacridone moieties was replaced by other intercalating groups, with the expectation that this would enhance biological activity while retaining the remarkable tissue selectivity and low systemic toxicity. The new compounds contain intercalating moieties such as 3-chloro-7-methoxyacridine or naphthalimide along with the original imidazoacridones.

These new compounds, especially those containing naphthalimide moiety, are extremely cytotoxic against variety of tumor cells in vitro (IC50 at low nanomolar range) and kill tumor cells by inducing apoptosis. In vivo, in nude mice xenografted with human tumors, the compounds significantly inhibited the growth of such tumors as colon tumor HCT116 and Colo205 as well as pancreatic tumors (lines 6.03 and 10.05 freshly established from a patient). These compounds are extremely potent agents against hepatocellular carcinoma as evidenced by their ability to eradicate liver cancer in an orthotopic liver cancer model in rats. Remarkably, no toxicity was observed at the therapeutic doses. These are among the most potent agents known against cancers of the GI tract and appear to be tolerated very well. CRADA Opportunity: The National Cancer Institute, Center for Cancer Research, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize imidazoacridones as therapeutic agents for cancer treatment. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Methods and Apparatus for Performing Multiple Simultaneous Manipulations of Biomolecules in a Two-Dimensional Array

Thu, 01 May 2003 13:00:00 GMT
This technology concerns a method and apparatus for accomplishing and/or facilitating the analysis of multiple biomolecules separated in a two-dimensional array, such as gel, membrane, tissue biopsy, etc. The invention employs a separator, termed an External Movement Inhibitor Device, that allows biomolecules to be transferred from an array such as those listed above to another support system while maintaining the two-dimensional spatial relationship of the biomolecules as in the array. The biomolecules can subsequently be subjected to various manipulations such as amplification, reverse transcription, labeling, cloning, etc., after which multiple well-established methods for quantitative and qualitative analysis can be used. CRADA Opportunity: The National Cancer Institute Laboratory of Pathology and Urologic Oncology Branch, Center for Cancer Research is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize an external movement inhibitor device for spatially-restricted PCR amplification of nucleic acids. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.

Use of E-Selectin Tolerization as Treatment for Immunological and Vascular-Related Disorders

Sun, 01 Apr 2001 17:00:00 GMT
This technology relates to the mucosal delivery (e.g. intranasal) of an E-selectin fragment as a tolerization agent for the prevention and treatment of immunological and vascular-related disorders, including stroke and multiple sclerosis (MS) as well as rare or orphan diseases involving vascular modulated disorders.

E-selectin is an adhesion molecule that is expressed on endothelial cells lining blood vessels in response to certain localized cytokines, making the endothelial surface pro-coagulant, pro-inflammatory and/or immunoreactive. Such changes on the endothelial surface have been linked to the development of vascular-related disorders like stroke, as well as immune regulated diseases such as MS.

Intranasal administration of E-selectin, using a tolerizing dosing schedule, induces an immunological tolerance to E-selectin. T regulatory cells become targeted to activating blood vessel segments, where they release immunomodulatory cytokines such as IL-10. This release of cytokines suppresses local pro-coagulant, pro-inflammatory and immunoreactive effects. Thus, administration of E-selectin as a tolerizing agent will provide a targeted therapeutic approach, impacting only affected sites in the endothelium. CRADA Opportunity: The Stroke Branch, NINDS/NIH, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize the applications of E-selectin tolerization in treatment of neurological based disease. For collaboration opportunities, please contact Laurie Arrants, NINDS at arrantsl@ninds.nih.gov.

Antitumor Immunity Elicited by Defensin-Tumor Antigen Fusions

Fri, 01 Dec 2000 22:00:00 GMT
Tumor antigens are known to be poorly immunogenic and attempts to elicit immune responses against the epitopes of antigens specific to tumor cells have been largely unsuccessful. The inventors have developed a cancer vaccine comprising a defensin fused to a tumor antigen or viral antigen to enhance the immunogenicity of the tumor antigen or viral antigen. The inventors have demonstrated, with animal data, that chimeric proteins, comprising a defensin fused to a model tumor antigen (lymphoma-derived single-chain Fv), when administered to a subject, generate a measurable humoral and anti-tumor cellular immune response. CRADA Opportunity: The National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize cancer vaccines comprising a defensin fused to tumor or viral antigens. For collaboration opportunities, please contact Nicole Guyton, Ph.D. at 301-435-3101 or darackn@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Metabolic Biomarkers Indicate Exposure to Gamma Radiation

Sun, 02 Jul 2000 02:00:00 GMT
Available for licensing and commercial development are methods of diagnosing exposure to gamma radiation in a mammal. Gamma radiation has both short-term and long-term adverse health effects including cancer. Urine samples collected from exposed mouse models irradiated at 0, 3, and 8 Gy (2.57 Gy/min) were analyzed by ultra-performance liquid chromatography-time of flight mass spectrometry (UPLC-TOFMS). Statistical analysis revealed that the following metabolomic markers were associated with exposure: 2'-deoxyxanthosine, xanthosine, 2'-deoxyuridine, 2'-deoxycytidine, N-hexanoylglycine and P-thymidine are urinary biomarkers of 3 and 8 Gy exposure. 3-hydroxy-2-methylbenzoic acid 3-O-sulfate and xanthine are elevated in urine of mice exposed to 3 but not 8 Gy, and taurine is elevated after 8 but not 3 Gy exposure. CRADA Opportunity: The National Cancer Institute, Laboratory of Metabolism, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the development of biomarkers for radiation gamma exposure and cell damage. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.